Clinical trial NCT02074436
Conditions: Hematological Malignancies Thrombocytopenia
Keywords: hematological malignancies thrombocytopenia aminocaproic acid
Sponsor: Emory University
Start date: 2014-05-23; Completion date: 2021-05-14
Enrollment: 29 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
STUDY BACKGROUND AND PURPOSE:

Patients with hematological malignancies (blood-related cancers) often develop thrombocytopenia (low platelet count), which can be made worse by cancer treatment.

Preventive (prophylactic) platelet transfusion remains the standard of care for thrombocytopenic patients. However, bleeding remains a significant problem in these patients, affecting approximately 20% of patients with acute myeloid leukemia and 34-58% of hematopoietic stem cell transplant recipients. Platelet transfusion refractoriness, the repeated failure to obtain satisfactory response to platelet transfusions, is a common problem. Alternatives to platelet transfusions are desperately needed for these patients.

Epsilon aminocaproic acid (EACA) blocks a process called fibrinolysis that is an essential step in the bleeding process. EACA is approved by the FDA for the treatment of severe bleeding-related diseases and complications. A small study has shown EACA to be well tolerated and associated with low risk of bleeding in patients with hematological malignancies.

This study will compare EACA versus standard prophylactic platelet transfusion for the prevention of bleeding in thrombocytopenic patients with hematological malignancies.

STUDY DESCRIPTION:

This is Phase II study to compare EACA versus standard prophylactic platelet transfusion to prevent bleeding in thrombocytopenic patients with hematological malignancies. Patients who are eligible to take part must give their written agreement before they can be enrolled.

The study will enroll 100 patients who will be assigned randomly to take EACA twice daily or to undergo standard prophylactic platelet transfusion. Patients will be followed for any bleeding events, need for platelet transfusion, and any side effects experienced. Patients will complete questionnaires to assess their quality of life while on the study.

Detailed description:
Study Treatments: Epsilon aminocaproic acid (EACA) vs. standard prophylactic platelet transfusions.

Study Title: Randomized Trial of Epsilon Aminocaproic Acid versus Platelet Transfusions for the Prevention of Bleeding in Thrombocytopenic Patients with Hematological Malignancies. (PROBLEMA trial: PRevention Of BLeeding in hEmatological Malignancies with Antifibrinolytic agents (epsilon aminocaproic acid).

Phase: Randomized Phase 2

Eligible Population: Adult patients with acute or chronic thrombocytopenia in the setting of hematological malignancies.

Summary and Study Rationale: Compare EACA to standard prophylactic platelet transfusion for the prevention of bleeding in thrombocytopenic patients with hematological malignancies.

Study Design: prospective, randomized, controlled trial.

Study Endpoints: The primary endpoint is to compare the proportion of patients who develop major (grades 3-4) bleeding in each arm.

Diagnosis and Main Inclusion Criteria: Age \> 18 with hematological malignancies. Acute or chronic thrombocytopenia with platelet counts \< 20 x 10⁹/L.

Number of Patients: 100 patients, 50 patients in each arm

Duration of Patient Participation: 6 months

Approximate Duration of Study: 3 years

Dosage and Administration:1,000 mg twice a day orally

Prohibited Medications/Treatment: Hydroxyurea and procoagulant agents including DDAVP, recombinant Factor VII or prothrombin complex concentrate are prohibited in patients receiving EACA.

Safety Evaluations: Clinical assessment once weekly during the first 30 days and then monthly for 6 months, complete blood count and bleeding score twice weekly the first 30 days, and then according to standard of care or at discretion of treating physician.

Statistical Analysis

* Population Analysis

  * Intention to treat (ITT) population: The ITT population includes all patients who are randomized to the study. Patients will be stratified and analyzed according to the treatment to which they were assigned.
  * Safety Population: The safety population includes all patients who have received at least 1 dose of EACA. Patients included in the safety population will be analyzed according to the treatment they received.
  * Per-protocol Population: The per-protocol population includes all patients who are randomized, receive at least one dose of study drug, and have no major protocol violations that could be expected to impact response data.
* Study Endpoints

  * Primary Endpoint: is to compare at the end of the study, the proportion of patients with major bleeding during the study period among patients randomized to receive either EACA or standard of care prophylactic platelet transfusions.
  * Secondary Endpoints include:

    * Proportion of patients with any bleeding during the study period in each arm
    * The total number of units of platelets transfused in each arm at the end of the study
    * Quality of life as measured in each arm before the study and at the end of the study
    * Safety in each arm
* Sample Size: This randomized, open-label phase II study is designed to compare the proportion of patient with major bleeding ever noted during the study. Patients will be assigned to receive prophylactic EACA (experimental arm) or prophylactic platelet (standard of care) in a 1:1 fashion. Previous studies suggest that the proportions of patients with major bleeding will be expected to be 8% and 30% in experimental arm and standard of care arm, respectively. With one sided Fisher's exact test, the sample size of 45 patients in each arm will achieve a power of 80% at the significance level of 5% to test whether prophylactic EACA can prevent major bleeding better than the standard of care. After adjusting for a 10% drop out rate, the actual required sample size will be 50 patients per arm. Therefore, the total sample size of the study will be 100 patients.
* Efficacy Analysis

  * Primary Endpoint Analysis will be performed using a one-sided Fisher's exact test to compare the proportions of patients with major bleeding during the whole study between the two arms. The significance level is set at 0.05. This primary analysis will be based on the ITT population.
  * Secondary Endpoint Analysis: one-sided t-test will be used to compare the total number of any bleeding episode noted during the study between the two arms. Two-sided t-test will be employed to compare the total number of units of platelets transfused at the end of the study between the two arms. Appropriate statistical tests (Chi-square test, t-test, Wilcoxon's rank sum test, etc.) will be conducted to compare the each score of the quality of life between the two arms before the study and at the end of the study, respectively. The change of each score of the quality of life from before the study to the end of the study will also be compared between the two arms. The safety in each arm will be also compared with Fisher's exact test. The analyses of secondary endpoints will be performed on the ITT population and the significance level will be kept at 0.05 for all tests.
* Safety Analysis: All patients receiving at least 1 dose of study drug will be considered evaluable for safety. Patients will be analyzed for safety according to the treatment which they received. Listings of laboratory test results will also be generated, and descriptive statistics summarizing the changes in laboratory tests over time will be presented. Exposure to study drug over time will also be summarized. The adverse events incidence rates, as well as the frequency of occurrence of overall toxicity, categorized by toxicity grades (severity) will be described for each treatment arm and be compared between two arms using two-sided Chi-square test or t-test.
* Quality of Life Analysis: Quality of life and health outcomes measures are being collected using EuroQoL instruments before the study and at the end of the study. Means and medians of raw scores of these questionnaires will be summarized for each treatment group for each domain and be compared between the two arms with t-test or Wilcoxon ranks sum test.
* Interim Analysis: Three interim analyses are planned after 11 patients in each arm have been randomized and their results have been obtained. Each interim analysis will focus on the primary endpoint, the proportion of patients with major bleeding ever noted during the study. To maintain an overall Type I error rate of 0.05 (1-sided), an O'Brien Fleming approach will be used which requires a 1-sided p-value \< 0.001 at the first interim analysis (at 25% of total sample size). If this boundary is not crossed, then the study will continue and the second interim analysis will be conducted at 50% of the total sample side which requires a 1-sided significance level of 0.004. If this boundary is not crossed at the second interim analysis then, the study will continue and a third interim analysis will be conducted at 75% of the total sample side which requires a 1-sided significance level of 0.019. If this boundary is not crossed, the final primary analysis will be performed after completing 100% of the sample size using a 0.043 one-sided significance level.

Arms: arm 1: Prophylactic EACA 1000 mg PO twice daily if platelets \< 20 x 10⁹/L arm 2: Platelet transfusion if platelet count is \< 20 x 10⁹/L in the outpatient or \< 10 x 10⁹/L in the inpatient setting
Interventions: intervention 1: EACA intervention 2: Platelet transfusion
Intervention descriptions: intervention 1: EACA 1000 mg twice a day. Patients will receive platelet transfusion in case of grade ≥ 2 bleeding. intervention 2: Prophylactic platelet transfusion. Additional platelet transfusions will be administered in case of grade ≥ 2 bleeding.

Protocol documents:
Prot_000.pdf: 
1
PROTOCOL AMENDMENT 5
Study Winship 2429
Winship 2429: Randomized Trial of Epsilon Aminocaproic Acid versus Platelet Transfusions for 
the Prevention of Bleeding in Thrombocytopenic Patients with Hematological Malignancies. 
(PROBLEMA trial: PRevention Of BLeeding in hEmatological Malignancies with Antifibrinolytic 
(epsilon aminocaproic acid).
Original Protocol Date:
October 18,2013
Amendment 1 Date:
February 18, 2015
Amendment 2 Date:
April 19, 2015
Amendment 3 Date:
August 25, 2015
Amendment 4 Date:
October 24,2016
Amendment 5 Date:
March 22, 2017
Section:
3.4 Description of Treatment and Study Schema
Additional information
count < 10 x109/L
Rationale:
Clarified in accordance with the standard of care in our institution that the 
platelet count threshold for platelet transfusions in the inpatient setting is
< 10 x109/L 
Section:
5.3 Study Duration and End of Treatment
Additional information
Subjects that completed treatment due to platelet count recover to > 30 x 
109/L on 2 measurements obtained 5 days apart whom  developed 
thrombocytopenia > 30 days of end of study and fulfill the inclusions and 
exclusion criteria are allowed to be re-enrolled in the study. Subjects 
without platelet recovery that completed 6 months of treatment are not 
allowed to be re-enrolled in the study
Rationale:
Clarified that subjects after recover platelet count can be re-enrolled in the 
study 
Section:
6.3.2
Dose Escalation


2
Original text
Patients randomized to EACA who experience persistent grade ≥ 2 oral 
bleeding secondary to acute or chronic gingivitis or mucositis who do not 
respond to chlorhexidine 0.12% oral rinse and antibiotic treatment 
(including but not limited to penicillin and metronidazole or amoxicillin 
and clavulanate or ampicillin and sulbactam or clindamycin), will receive 
platelet transfusions as per standard of care and have the option of 
increasing the dose of EACA to 1,000 mg three times a day. If the dose of 
1,000 mg TID is poorly tolerated, then the EACA will be held and restarted 
at 1,000 mg BID after resolution of the AEs to < grade 1. 
Patients randomized to EACA who have persistent cutaneous bruises will 
receive platelet transfusions as per standard of care and have the option of 
increasing the dose of EACA to 1,000 mg three times a day. If the dose of 
1,000 mg TID is poorly tolerated, then the EACA will be held and restarted 
at 1,000 mg BID after resolution of the AEs to < grade 1. If bruising 
continues, patient will be taken off study.  
Modified text
Patients randomized to EACA who experience any persistent grade ≥ 2 
bleeding including  hematuria, will receive platelet transfusions as per 
standard of care and have the option of increasing the dose of EACA to 
1,000 mg three times a day. If the dose of 1,000 mg TID is poorly tolerated, 
then the EACA will be held and restarted at 1,000 mg BID after resolution 
of the AEs to < grade 1. 
If patient experience oral bleeding secondary to acute or chronic gingivitis 
or mucositis who do not respond to chlorhexidine 0.12% oral rinse and 
antibiotic treatment (including but not limited to penicillin and 
metronidazole or amoxicillin and clavulanate or ampicillin and sulbactam 
or clindamycin), then have the option of increasing the dose of EACA to 
1,000 mg three times a day. If the dose of 1,000 mg TID is poorly tolerated, 
then the EACA will be held and restarted at 1,000 mg BID after resolution 
of the AEs to < grade 1. 
Rationale:
Clarify that dose escalation is allowed for any bleeding grade ≥ 2 instead 
only for oral and cutaneous bleeding.
Section: Table 3
3.5 Study Schema
Changes
1-Screening period was changed to < 21 days instead of -21 to -1.
2- ±3days was removed from Day 1
3- A foot note was added to clarify that the diary card will be completed by 
arm B-EACA
Rationale:
Clarification for more efficient data entry and avoid duplication
Consent Changes
Procedures Table
1-Screening period was changed to < 21 days instead of -21 to -1.
2- ±3days was removed from Day 1
3- A foot note was modified in accordance with protocol


3
Study Title: 
Winship 2429: Randomized Trial of Epsilon Aminocaproic Acid versus Platelet 
Transfusions for the Prevention of Bleeding in Thrombocytopenic Patients with Hematological 
Malignancies. (PROBLEMA trial: PRevention Of BLeeding in hEmatological Malignancies with 
Antifibrinolytic (epsilon aminocaproic acid).
Study Phase: 
Randomized Phase 2                   
Principal Investigator: Ana Antun, MD 
Co-Investigator: 
H. Jean Khoury, MD    
Product Name: 
epsilon aminocaproic acid (EACA)
IND Reference Number:119,487
Sponsor: 
N/A
Protocol Date:
 March 22, 2017
Version Number: 
Version  9.0
PROTOCOL REVISION HISTORY:
Protocol Version Number
Date
Version 2.0
July 29, 2013
Version 3.0
August 20, 2013
Version 4.0
October 18, 2013
Version 5.0
February 18, 2015
Version 6.0
April 19, 2015
Version 7.0
August 25, 2015
Version 8.0
October 24, 2016
Version 9.0
March 22, 2017


4
PROTOCOL SYNOPSIS
Study Treatments
Epsilon aminocaproic acid vs. standard prophylactic 
platelet transfusions
Study Title
Randomized Trial of Epsilon Aminocaproic Acid versus 
Platelet Transfusions for the Prevention of Bleeding in 
Thrombocytopenic 
Patients 
with 
Hematological 
Malignancies. 
(PROBLEMA 
trial: 
PRevention 
Of 
BLeeding 
in 
hEmatological 
Malignancies 
with 
Antifibrinolytic (epsilon aminocaproic acid).
Phase
Randomized Phase 2
Eligible Population
Adult patients with acute or chronic thrombocytopenia in 
the setting of  hematological malignancies
Summary and Study Rationale
Compare EACA to standard prophylactic platelet 
transfusion 
for 
the 
prevention 
of 
bleeding 
in 
thrombocytopenic 
patients 
with 
hematological 
malignancies 
Study Design
prospective, randomized, controlled trial
Study Endpoints
The primary endpoint is to compare proportion of 
patients who develop major (grades 3-4) bleeding in each 
arm.
Diagnosis and Main Inclusion Criteria
Age > 18  with hematological malignancies
Acute or chronic thrombocytopenia with platelet counts < 
20 x 109/L 
Number of Patients
100 patients, 50 patients in each arm
Duration of Patient Participation
6 months
Approximate Duration of Study
3 years
Dosage and Administration
1,000 mg twice a day orally 
Prohibited Medications/treatment
Hydroxyurea and procoagulant agents including DDAVP, 
recombinant FVII or prothrombin complex concentrate 
are prohibited in patients receiving EACA
Safety Evaluations
Clinical assessment once weekly during the first 30 days 
and then monthly for 6 months, CBC and bleeding score 
twice weekly the first 30 days, and then according to 
standard of care or at discretion of treating physician.
Statistical Analysis
Population Analysis 
Intention to treat (ITT) population: The ITT population 
includes all patients who are randomized to the study. 
Patients will be stratified and analyzed according to the 
treatment to which they were assigned. 
Safety Population: The safety population includes all 
patients who have received at least 1 dose of EACA. 
Patients included in the safety population will be analyzed 
according to the treatment they received.
Per-protocol Population: The per-protocol population 
includes all patients who are randomized, receive at least 
one dose of study drug, and have no major protocol 
violations that could be expected to impact response data.
Study Endpoints


5
-
Primary Endpoint: is to compare at the end of the 
study, the proportion of patients with major bleeding 
during the study period among patients randomized 
to receive either EACA or standard of care 
prophylactic platelet transfusions.
-
Secondary Endpoints include:

proportion of patients with any bleeding during 
the study period in each arm

the total number of units of platelets transfused in 
each arm at the end of the study

Quality of life as measured  in each arm before the 
study and at the end of the study

Safety in each arm
Sample Size 
This randomized, open-label phase II study is designed to 
compare proportion of patient with major bleedings ever 
noted during the study. Patients will be assigned to 
receive prophylactic EACA (experimental arm) or 
prophylactic platelet (standard of care) in a 1:1 fashion. 
Previous studies suggest that the proportions of patients 
with major bleeding will be expected to be 8% and 30% 
in experimental arm and standard of care arm, 
respectively. With one sided Fisher’s exact test, the 
sample size of 45 patients in each arm will achieve a 
power of 80% at the significance level of 5% to test 
whether prophylactic EACA can prevent major bleeding 
better than the standard of care. After adjusting for a 
10% drop out rate, the actual required sample size will be 
50 patients per arm. Therefore, the total sample size of 
the study will be 100 patients. 
Efficacy Analysis
-
Primary Endpoint Analysis will be performed using a 
one-sided fisher exact test to compare the proportions 
of patients with major bleeding during the whole 
study between the two arms. The significance level is 
set at 0.05. This primary analysis will be based on the 
ITT population.
-
Secondary Endpoint Analysis: one-sided t-test will be 
used to compare the total number of any bleeding 
episode noted during the study between the two arms. 
Two-sided t-test will be employed to compare the total 
number of units of platelets transfused at the end of 
the study between the two arms. Appropriate 
statistical tests (Chi-square test, t-test, Wilcoxon’s 
rank sum test, etc.) will be conducted to compare the 
each score of the quality of life between the two arms 
before the study and at the end of the study, 
respectively. The change of each score of the quality of 


6
life from before the study to the end of the study will 
also be compared between the two arms.  The safety 
in each arm will be also compared with Fisher’s exact 
test. The analyses of secondary endpoints will be 
performed on the ITT population and the significance 
level will be kept at 0.05 for all tests.
Safety Analysis
All patients receiving at least 1 dose of study drug will be 
considered evaluable for safety. Patients will be analyzed 
for safety according to the treatment which they received. 
Listings of laboratory test results will also be generated, 
and descriptive statistics summarizing the changes in 
laboratory tests over time will be presented. Exposure to 
study drug over time will also be summarized. The AE 
incidence rates, as well as the frequency of occurrence of 
overall toxicity, categorized by toxicity grades (severity) 
will be described for each treatment arm and be 
compared between two arms using two-sided Chi-square 
test or t-test.
Quality of Life Analysis
Quality of life and health outcomes measures are being 
collected using EQ-5D-5L instruments before the study 
and at the end of the study. Means and medians of raw 
scores of these questionnaires will be summarized for 
each treatment group for each domain and be compared 
between the two arms with t-test or Wilcoxon ranks sum 
test.
Interim Analysis
 Three interim analyses are planned after 11 patients in each 
arm have been randomized and their results have been 
obtained. Each interim analysis will focus on the primary 
endpoint, the proportion of patients with major bleeding ever 
noted during the study. To maintain an overall Type I error 
rate of 0.05 (1-sided), an O’Brien Fleming approach will be 
used which requires a 1-sided p-value < 0.001 at the first 
interim analysis (at 25% of total sample size). If this 
boundary is not crossed, then the study will continue and the 
second interim analysis will be conducted at 50% of the total 
sample side which requires a 1-sided significance level of 
0.004. If this boundary is not crossed at the second interim 
analysis then, the study will continue and a third interim 
analysis will be conducted at 75% of the total sample side 
which requires a 1-sided significance level of 0.019. If this 
boundary is not crossed, the final primary analysis will be 
performed after completing 100% of the sample size using a 
0.043 one-sided significance level.


7
TABLE OF CONTENTS
Protocol Synopsis
1.
Background
1.1 Thrombocytopenia in Patients With Hematological Malignancies
1.2 Fibrinolysis and Inhibition of Fibrinolysis with Epsilon Aminocaproic Acid
1.3 Preliminary studies
1.4 Rationale for the study
2.
Study Objectives and Hypothesis 
2.1 Primary Objective
2.2 Secondary Objective
2.3 Hypothesis
3.
Investigational Plan:
3.1 Overall Study Design and Plan
3.2 Primary Endpoint
3.3 Secondary Endpoint
3.4 Description of Treatment
3.5 Randomization
4.
Selection of Study Population
4.1 Inclusion Criteria
4.2 Exclusion Criteria
5.
Study Procedures
5.1 Schedule of Events
5.2 Patient Registration and Identification
5.2.1
Screen Failure
5.2.2
Early Discontinuation
5.3 Study Duration and End of Treatment
5.4 Withdrawal Criteria
5.5 Study Termination
6.
Safety and Quality of Life Assessments 
6.1 Safety Assessment
6.1.1
Adverse events
6.2 Quality of Life Assessments
Study Treatments
6.3 Study Treatments
6.3.1
Dose Selection, Treatment Administration and Compliance 


8
6.3.1.1 EACA
6.3.1.2 Prophylactic Platelet Transfusions
6.3.1.3 Therapeutic Platelet Transfusions 
6.3.2
Dose Escalation
6.3.3
Management of Adverse Events and Dose Modifications
6.4 Allocation of Treatment
6.5 Concomitant Medications
6.5.1
Permitted Medications
6.5.2
Prohibited Medications
6.5.3
Treatment Supply
6.5.3.1 Formulation, Packaging and Labeling
6.5.3.2 Treatment Storage, Dispensing, and  Accountability
6.5.3.2.1
Disposition of used supplies
6.5.3.2.2
Disposition of unused supplies
7.
Adverse Events Reporting
7.1 Adverse Events
7.1.1
Adverse Event Definition
7.1.2
Abnormal Laboratory Tests
7.1.3
Performing Adverse Event Assessment
7.1.4
Reporting Period
7.1.5
Adverse Event Severity 
7.1.6
Causality
7.1.7
Expectedness
7.2 Serious Adverse Events
7.2.1
Serious Adverse Event Definition
7.2.2
Reporting Serious Adverse Events
7.2.3
Follow-up Information of Serious Adverse Events
7.3 Other Safety Issues
7.3.1
Pregnancy
7.3.2
Overdose 
7.4 Unanticipated Problems 
8.
Statistical Considerations
8.1 General Considerations
8.2 Analysis Population
8.3 Study Endpoints
8.3.1
Primary Endpoint
8.3.2
Secondary Endpoint
8.4 Determination of Sample Size 
8.5 Efficacy Analysis
8.5.1
Definition of Efficacy Endpoints
8.5.2
Primary Endpoint Analysis
8.5.3
Secondary Endpoint Analysis


9
8.6 Safety Analysis
8.7 Quality of Life Analysis
8.8 Interim Analysis
8.8.1
Impact on Conduct of Study
8.9 Protocol Deviations and Violations
9.
Quality Control and Quality Assurance and Study Monitoring 
10. Ethical Conduct of the Study
10.1
Institutional Review Boards Approval
10.2
Patient Information and Consent
10.3
Patient Confidentiality
10.4
Data Safety Monitoring Committee
11. Data Handling and Record Keeping
11.1
Case Report Forms and Study Records
11.2
Source Documents
11.3
Retention of Data 
11.4
Study Termination
12. References 


10
Background
1.1 Thrombocytopenia in Patients with Hematological Malignancies
Thrombocytopenia is a very common problem in patient with hematological malignancies and marrow 
failure syndromes, and is often worsened by the myelosuppressive side-effects of cytotoxic therapies. 
Despite advances in transfusion medicine and optimization of prophylactic platelet transfusions, bleeding 
remains a significant problem in these patients affecting approximately 20% of patients with acute 
myeloid leukemia and 34-58% of hematopoietic stem cell transplant (HSCT) recipients. [1] [2]
Prophylactic allogeneic platelet transfusion remains the standard of care practice for thrombocytopenic 
patients. Given the prolonged duration of thrombocytopenia in patients with hematological malignancies, 
several studies were conducted to identify the lowest safe platelet threshold for transfusion, and the 
optimal platelet dose. Three randomized trials were conducted in an attempt to identify the lowest safe 
platelet threshold for platelet transfusion. [3] [4]. Based on the results of these studies, a platelet count of 
10 x 109/L is the accepted prophylactic transfusion trigger when patients are hospitalized in the in-
patient unit, while 20 x 109/L is the accepted threshold for the out-patient.
Platelet refractoriness is very common in patients with hematological malignancies and marrow failure 
syndromes. Platelet transfusion refractoriness, defined as a repeated failure to obtain satisfactory response 
to platelet transfusions or increase in percentage of platelet recovery less than 20-30% at 1 hour post 
transfusion or 10-20% after 20-24 hour, [5]   is a significant problem occurring in 7-34 %.  [6] [7] [8]    HLA 
matched platelet transfusions are commonly prescribed in patients with platelet refractoriness; and 
although effective in some cases,  this rather complex, time consuming, and expensive procedure is highly 
dependent of platelet donor availability. So maintaining platelet counts in a safe range is practically 
impossible in these platelet refractory profoundly thrombocytopenic patients due to severe 
shortening of the platelet survival.
1.2 Fibrinolysis and Inhibition of Fibrinolysis with Epsilon Aminocaproic Acid (EACA) 
1.2.1
Fibrinolysis: After vessel injury, platelet aggregation and activation of the coagulation cascade 
pave the way for the generation of thrombin, an essential element for thrombus formation. 
Thrombin then converts fibrinogen to fibrin, the basic “mesh” that is required for endothelium 
repair. In order to prevent uncontrolled clot formation, tissue plasminogen activator is released by 
the endothelium, which then converts plasminogen to plasmin and degrades fibrin into fibrin 
degradation products. This process, called fibrinolysis is a key element that limits the propagation 
of intravascular thrombi. (Figure 1)


11
1.2.2
Inhibition of Fibrinolysis with EACA: EACA is a synthetic monaminocarboxylic acid that 
effectively inhibits fibrinolysis by preventing the binding of plasmin to fibrin.

Pharmacologic properties of EACA: EACA is orally bioavailable, rapidly and completely 
absorbed from the GI tract, with a peak plasma concentration attained within an hour. Sustained 
plasma concentration can be maintained by repeated oral dosing or by continuous IV infusion. A 
plasma concentration of 130 mcg/ml appears necessary to maintain inhibition of systemic 
fibrinolysis and this plasma concentration reportedly should be attained and sustained by IV 


12
administration of a 5 g loading dose followed by continues IV infusion of 1-1,25 g per hour. The 
terminal elimination half-life is approximately 2 hours. The 40-45% of a single oral or IV dose is 
excreted in urine as unchanged drug within 12 hours and approximately 11% is excreted as the 
metabolite adipic acid. Renal clearance of the drug approximates endogenous creatinine clearance 
and has been reported to be 116 ml/min. EACA is removed by hemodialysis and may be removed 
by peritoneal dialysis. 

Approved indications for the use of EACA:  EACA is approved by the FDA for  treatment of 
surgical bleeding complications following heart surgery (with or without cardiac bypass 
procedures) and portacaval shunt; hematological disorders such as amegakaryocytic 
thrombocytopenia (accompanying aplastic anemia); acute and life-threatening abruptio placentae; 
hepatic cirrhosis; and neoplastic disease such as carcinoma of the prostate, lung, stomach, and 
cervix. Bleeding associated with surgical hematuria (following prostatectomy and nephrectomy) 
or nonsurgical hematuria (accompanying polycystic or neoplastic diseases of the genitourinary 
system secondary to urinary fibrinolysis). Platelet dysfunction and von Willebrand, menorrhagia, 
gastrointestinal tract bleeding, nose and mouth bleeds and coagulation defects such as 
hemophilia. In the acute bleeding setting, EACA is administered orally or by IV infusion, at an 
initial dose of 4-5g during the first hour of treatment, followed by 1-1.25g/hour in order to sustain 
the plasma concentration of the drug at 130 mcg/ml. Maximum dose recommended is 30 g/24 
hours. When the bleeding tendency is chronic in nature, a dosage of 5-30g, for 5 days is generally 
used although lower daily dosage may also be effective.

Side effects associated with the use of EACA and precautions: Table 1 summarizes side effects 
reported with the use of EACA. Thrombotic complications are rare with the use of EACA, but 
have been reported in a patient with hemophilia receiving concomitant therapy with factor IX. 
EACA may accumulate in patient with decreased renal function, and dose-reduction is 
recommended. EACA is contraindicated in patients with hematuria originating from the upper 
urinary tract due to intrarenal obstruction via glomerular capillary thrombosis or clots. In patient 
receiving long term therapy at doses > 10 g/d, elevations of serum creatine kinase concentrations 
due to skeletal myopathy were reported.

Contraindications for the use of EACA: EACA should not be used when there is evidence of an 
active intravascular clotting process. EACA must not be used in the presence of disseminated 
intravascular coagulopathy (DIC) without concomitant heparin. 
In summary EACA is safe and effective therapy that enhances hemostasis in patients with 
congenital bleeding disorders and bleeding complicating certain medical conditions and 
surgical procedures.


13
Table 1. Common Adverse Events reported with the use of EACA and Potential risks [9]    
System organ 
class
Common
(>1/100 or 
<1/10)
Uncommon
(>1/1,000 or 
<1/100)
Rare
(>1/10,000 or 
<1/1,000)
Very Rare
<1/10,000
Not known
Blood and 
lymphatic system 
disorder
Agranulocytosis,
clotting disorders
Leukopenia,
thrombocytopenia
Immune
System
Disorder
Allergic and 
anaphylactoid 
reactions,
Anaphylaxis
Maculopapular
erythema
Nervous
System
Disorders
dizziness
Confusion,
Seizures,
Delirium,
Hallucinations,
Intracranial ,
Hypertension,
Stroke, syncope.
Eye disorders
Reduce vision,
Watery eyes
Ear and 
Labyrinth
Disorders
Tinnitus
Cardiac
Disorders
Hypotension
Bradycardia
Peripheral 
ischemia
Thrombosis
Respiratory,
Thoracic and 
mediastinal 
disorders
Nasal congestion
dyspnea
Pulmonary 
embolism
Gastrointestinal
disorders
Abdominal
Pain,
Diarrhea,
Nausea,
Vomiting
Skin and
Subcutaneous
tissue disorders
Pruritus, rash
Musculoskeletal 
And  connective
tissue disorders
Muscle
Weakness,
myalgia
Elevated CPK,
Myosis
Acute myopathy,
rhabdomyolysis
Renal and 
Urinary 
disorders
Renal failure,
BUN increased,
Nephritic colics
and kidney 
function disorders
Reproductive
system and 
breast disorders
Dry ejaculation
General
disorders and
administration
site conditions
Headache,
Malaise,
Injection site 
reaction,
Pain and necrosis
Edema
*frequency not known (cannot be estimated from the available data)


14
1.3. Preliminary Studies 
We analyzed the outcomes of 44 patients with hematological malignancies and marrow failure syndromes 
who received EACA for the prevention of bleeding, and as a platelet transfusion sparing agent.  EACA 
was given continuously for a median of 47 days, but up to 7 months, at the oral dose of 1 gram twice 
daily until platelets recovered to > 30 x 109/L. Platelets were only transfused in case of bleeding .While 
on EACA 59% did not bleed, 25% had 19 episodes of spontaneously resolving minor mucocutaneous 
bleeds for which they did not require platelet transfusion, and 16% received a median of 4 platelet 
transfusions to treat 1 major traumatic and 9 spontaneous grade 2 –3 bleeding. Table 2 EACA was well 
tolerated and venous thrombosis were not observed.  EACA was safe, well tolerated and associated with a 
low risk of major bleeding in chronic severe thrombocytopenic patients with hematological malignancies.
1.4 Rationale for the Conduct of this Study
Given the high incidence of platelet refractoriness, and the prolonged duration of thrombocytopenia in 
patients with hematological malignancies and marrow failure syndromes, alternatives to platelet 
transfusions are desperately needed. Our institutional experience with EACA provides a unique expertise 
to further investigate the role EACA can play in the prevention of bleeding in this patient population. We 
therefore propose to conduct a prospective, randomized, controlled trial to compare EACA versus 
standard prophylactic platelet transfusion to prevent bleeding in thrombocytopenic patients with 
hematological malignancies. The objectives of the trial are to address safety and efficacy of EACA as 
assessed by major and minor bleeding, cumulative platelet transfusion consumption, quality of life and 
costs in both arms of the study.
Table 2:  Characteristics of 44 thrombocytopenic patients who received epsilon aminocaproic acid 
for the prevention of bleeding
Age, years median  (range) 
61 (17-82)
Male/female
29/15
Platelet counts x109/L when EACA started, median (range)
8  (1 – 19)
Patients with platelet refractoriness n (%)
10 (23%)
Duration of thrombocytopenia in days, median (range)
273 (20-1463)
Diagnosis n (%)
CML
AML
ALL
MDS
CLL
ITP
Lymphomas
Aplastic anemia
Myelofibrosis
9 (21)
14 (32)
1 (2)
15 (35)
1 (2)
1 (2)
1 (2)
1 (2)
1 (2)
Disease Status of patients at the time  EACA started
 Active treatment, n (%)
   Relapsed/refractory, n (%)
13 (29) 
31 (71)
Duration of EACA therapy,median(range) in days
47 (7-209)
Patients without bleeding on EACA, n (%)
26 (59)
Patients with bleeding episodes while on EACA, n (%) 
Patients requiring platelet transfusions for bleeds, n (%)
18 (41)
7 (16%)
Grade and location of the 10 bleeding episodes requiring 
platelet transfusions:
Grade 4 – CNS*
1


15
Grade 3 – rectal
Grade 2 – hemorrhoids 
Grade 2 – hematuria **
Grade 2 – epistaxis
Grade 2 – oral
Grade 2 – vaginal
1
1
2
1
3
1
Grade and location of the 19  bleeding episodes not 
requiring platelet transfusions:
Grade 1-  epistaxis
Grade 1 – skin bruises
Grade 1 – gingival bleed
Grade 1 - vaginal 
Grade 2 – gingival
Grade 2 – vaginal
Grade 2 - epistaxis
7
4
2
1
2
1
2
Reason for discontinuing EACA, n (%)
   Death
   Increased platelets count
   Hematuria
25 (57)
18 (41)
1 (2) 
*Traumatic brain injury in a car accident
**One patient had 2 episodes of hematuria
2
Study Objectives and Hypothesis
2.1.Primary Objective: 
The primary objective of this study is to compare the proportion of patients who develop major 
bleeding episodes (WHO grades 3-4) in the group randomized to receive prophylactic EACA versus 
standard of care prophylactic platelet transfusions.
2.2 Secondary Objectives: 

To compare the proportion of patients who develop any bleeding episode in the group randomized 
to receive prophylactic EACA versus standard of care prophylactic platelet transfusions.

To compare, according to treatment with prophylactic EACA or prophylactic platelet transfusions, 
the total number of units of platelet transfused 

To compare the quality of life in both arms of the study
2.3 Hypothesis:
This is a non-inferiority trial in which we hypothesize that in thrombocytopenic patients with 
hematological malignancies, comparable incidence of bleeding will be observed with the prophylactic use 
of EACA and standard of care arm prophylactic platelet transfusions. 
3.
Investigational Plan
3.1.Overall Study Design and Plan:
This is a single center, randomized phase 2, open label trial of oral EACA versus platelet transfusions 
for the prevention of bleeding in thrombocytopenic patients with hematological malignancies. 


16
Eligible patients with acute or chronic thrombocytopenia will be randomized in a 1:1 fashion to 
receive oral EACA at the dose of 1,000 mg twice daily as a substitute for prophylactic platelet 
transfusions or standard of care prophylactic platelet transfusions for an untransfused  platelet count < 
20 x109/L in the out-patient or in the in-patient setting. Patients will be assessed twice weekly and as 
needed in between visits for the presence of bleeding. The number of platelets transfused for 
prophylaxis (arm B) or for therapeutic purposes (both arms) will be monitored. Patients will complete 
quality of life questionnaire. Adverse events will be assessed and graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Bleeding 
will be assessed and graded according to the World Health Organization (WHO) classification 
[Appendix 1]. Patients will be assessed according to a protocol-specific schedule of events. Patients 
will continue treatment on trial until one or more criteria for discontinuation are met. Patients will be 
supplied with study drug until they discontinue from the study. Patients will be followed for 2 years 
or death, whichever occurs first.  
3.2.Primary Endpoint:
The primary endpoint is to compare the proportion of patients who develop major bleeding (WHO 
grade 3 or 4) in each arm.
3.3.Secondary Endpoints:
Secondary endpoints include:

The proportion of patients who develop any bleed in each arm

The total number of units of platelets transfused in each arm during the study period 

Quality of life as measured by EQ-5D-5L in each arm prior to start treatment and at the end 
of the study

Safety in each arm
3.4.Description of Treatment:
Patients will be stratified by expected duration of thrombocytopenia (acute versus chronic), and 
randomized to receive oral EACA at the dose of 1,000 mg twice daily or the infusion of 1 U of single 
donor apheresis of platelet when untransfused platelet counts are < 20x109/L in the out-patient or < 10 
x109/L in the in-patient, as measured on at least twice weekly CBCs (standard of care for cytopenic 
patients). Schema of the trial is listed in Figure 3. 


17
Study Schema.  
                                                       
                                          
                                                       
                                                                                                                                                                                                     
3.5.Randomization:
Patients will be randomized on a 1:1 ratio within each strata (acute vs. chronic) to EACA (Arm B) or 
standard prophylactic platelet transfusions (Arm A) using a standard randomization table. The study 
is unblinded. 
4.
Patient  Selection: 
4.1. Inclusion Criteria:

Age > 18 with a hematological malignancy

Informed consent 

Thrombocytopenia with untransfused platelet counts < 20 x 109/L in the out-patient or in the in-
patient setting and one of the following criteria:
1.
Acute thrombocytopenia in  patients with hematological malignancies who are in remission and 
are receiving myelosuppressive consolidation chemotherapy that is expected to induce marrow 
aplasia for at least 2 weeks; or
2.
Acute or chronic thrombocytopenia in patients with acute leukemia (myeloblastic o 
lymphoblastic)  receiving induction  or re-induction chemotherapy that is expected to induce 
marrow aplasia for at least 2 weeks; or Expected chronic thrombocytopenia in patients with 
newly diagnosed marrow failure syndromes, myelodysplastic syndromes, aplastic anemia, 
chronic myelomonocytic leukemia or myelofibrosis; or
3.
Expected chronic thrombocytopenia in patients with relapsed or refractory hematological 
malignancies; or
Subject consented, screened and enrolled
Randomization
Eligible patients with hematological malignancies with 
asymptomatic untransfused platelet count < 20,000/l
Platelet transfusion if platelet count is < 20x109/L 
in the outpatient or < 10x109/L in the inpatient setting
Prophylactic EACA 1000 mg PO BID 
if platelets < 20x109/L 
Assessment for bleeding, tracking of platelets transfusions, QOL 
questionnaire
ARM (A)
ARM (B)


18
4.
Hematopoietic stem cell transplant recipients with chronic thrombocytopenia due to chronic 
GVHD or other  causes.
4.2 Exclusion Criteria:

Acute promyelocytic leukemia

Patient receiving anticoagulation 

Patient receiving antiplatelet  agents

Patient treated with antifibrinolytic agents (including EACA) within 14 days prior to screening.

Subjects receiving procoagulant agent including DDAVP, recombinant FVII or prothrombin 
complex concentrate within 24 hours of enrollment

Subject with known congenital bleeding disorders or platelet dysfunction

Disseminated intravascular coagulation 

Fibrinogen level < 150 mg/dl

Patients with known lupus anticoagulant or positive antiphospholipid antibody

History of arterial or venous thromboembolic disease 6 months prior to screening  

Patient requiring platelet transfusion threshold of > 20x109/L

Active grade > 2 bleeding at the time of randomization, including hematuria

History of grade 4 bleeding 

Hematopoietic stem cell transplant recipient within 100 days post-transplant

Pregnancy

Known allergy to EACA

History of veno-occlusive disease of the liver

Myocardial infarction 6 months prior to screening  

Unstable angina

Grade 2 renal dysfunction: creatinine > 2-3 times the upper limit of normal
5. Study Procedures
5.1 Schedule of Events
Table 3. Screening and study procedures to be done through the end of the study. Evaluation visit 
samples or activities should occur within 3 days of the scheduled study day
Screening
Cycle 1
Monthly
(until Month 
6)
End of 
treatment
Day <21 
Day 1
Day 8
±3days
Day 15
±3days
Day 22
±3days
Day 1
±3days
Informed Consent
X
History and Demographics
X
Hematological disorder                      
diagnosis and prior therapy
X
Urine HCG
X
Vital Signs, ECOG PS and 
Physical Examination
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X


19
Randomization
X
CBC*
X
X
X
X
X
X
X
Fibrinogen
X
Comprehensive metabolic 
panel**
X
X
X
X
X
X
X
Patient’s questionnaire QOL
X
X
Transfusions records
X
X
X
X
X
X
Diary card***
X
X
X
X
X
X
Bleeding score WHO*
X
X
X
X
X
X
X
AE’s
X
X
X
X
X
X
SAE
X
X
X
X
X
X
*First 30 days , i.e.: twice weekly or at the discretion of the treating physician, but at least once a week.(If the decision is twice a week, the 
non-visit day bleeding score may be assessed in person or by  phone). After 30 days CBC and bleeding score will be performed according to 
the standard of care for cytopenic patients **glucose, serum calcium, blood urea nitrogen, creatinine, sodium, potassium, chloride, serum 
albumin, serum total proteins, carbon dioxide, alkaline phosphatase, aspartate amino transferase and alanine amino transferase. The 
screening procedures including blood and urine test obtained as part of the routine care, up to 72 hours prior to  consenting, may be used 
to qualify the subject for eligibility and randomization. *** Diary card to be completed by Arm B - EACA 
The following describes the procedures/tests required for this study:
Informed Consent: All patients must take part in the informed consent process prior to any study related 
activity. During the consent process, the person obtaining consent must inform the patient of all elements 
of informed consent. Adequate time must be allowed for questions and for the patient to make a voluntary 
decision. No protocol-specific procedures are to be performed until the patient has signed and dated the 
IRB approved informed consent form. Each patient's participation in the trial begins with the signing and 
dating of the informed consent form.
Screening: Screening tests and procedures are used to establish eligibility of the patient for the trial. 
Patients must continue to maintain laboratory values within eligibility parameters if any given procedure 
or laboratory test is repeated prior to randomization. All screening tests must be done within 7 days prior 
to randomization.
Randomization: Randomization procedure will be performed following complete eligibility assessments 
and just prior to the initiation of assigned treatment.
Medical/Surgical History and Demographics: Medical and surgical history and demographic information 
will be recorded. Medical and surgical history includes diagnoses, therapies, medical and surgical 
treatments, and current medications. Demographic information consists of the patient’s age, gender, race, 
and ethnicity.
Hematological Disorder Diagnosis: The initial hematological diagnosis including the date of onset of the 
diagnosis must be recorded.
Vital signs and Physical Examination: Vital signs are temperature, pulse, respiratory rate, and blood 
pressure. A complete physical examination, including weight, must be performed at screening, prior to the 
first administration of study drug, and at the End-of-Treatment Visit. All subsequent physical 
examinations are part of the standard of care but should be directed to relevant bleeding findings in the 
patient. 


20
Complete Blood Count (CBC): CBC with differential is defined as peripheral blood total white blood cell 
(WBC) count, hemoglobin, hematocrit, and platelet count. This is a standard of care test obtained 
routinely in all patients with hematological disorders.
Chemistry (Comprehensive metabolic panel): is a set of 14 chemical test including sodium, potassium, 
chloride, bicarbonate, blood urea nitrogen, creatinine,  glucose, serum calcium,  serum albumin, serum 
total proteins, carbon dioxide, alkaline phosphatase, aspartate amino transferase and alanine amino 
transferase
EQ-5D Assessments: The EQ-5D-5L will be used to collect patient-assessed quality of life and health 
outcomes measures. Patients are required to complete the instruments if there is a validated translation in 
a language in which they are fluent.
Bleeding score: Bleeding will be graded according with the WHO bleeding scale (Appendix 1) and 
recorded in the medical records during each visit. For hospitalized subjects enrolled on this trial, bleeding 
will be described in the daily follow up note by physician, nurse practitioner or physician assistant and 
graded by the investigator. 
End of Treatment or Early Termination Procedures: The End-of-Treatment (or early termination) Visit 
should be performed within 2 weeks (14 days) of the patient’s last dose of study drug or the 
patient/investigator decision to end treatment, whichever is later.
Follow-up Procedures: Safety: All AEs ongoing or starting within 30 days after the End-of-Treatment 
must be recorded on the CRF. After this time, ongoing AEs thought to be at least possibly study-drug 
related and all ongoing SAEs should be followed at least every 4 weeks until they resolve to baseline (or 
CTCAE grade ≤1), stabilize, or are considered to be chronic or irreversible.
Follow-up Procedures: Survival: Survival data will be collected every 12 weeks ± 2 weeks starting after 
the last dose of the assigned study treatment or the investigator/patient decision to discontinue treatment, 
whichever occurs later and continuing for up to 12 months from the time the last patient is randomized to 
a treatment group. These data do not need to be obtained during a visit; phone contact is acceptable.
5.2 Patient Registration and Identification
Demographic information on all patients who sign the Informed Consent Form will be recorded on the 
master subject log. Those patients who complete screening procedures and meet all eligible criteria may 
be enrolled. At the time of enrollment, the patient will be assigned a unique identification code (number), 
consisting of a study site number and a unique consecutive number.
5.2.1 Screen Failure
Patients who have signed informed consent and subsequently fail to meet the inclusion and/or exclusion 
criteria are defined as screen failures. For all screen failures, the Investigator is to maintain a screening 
log that documents the patient initials and reason(s) for screen failure. A copy of the log will be retained 
in the Investigator’s study files. Any patient who is rescreened after screen failure must, in addition to the 
failed procedure, repeat only those screening procedures outlined in the Schedule of Events that have 
fallen outside the specified screening period.
5.2.2 Early Discontinuation


21
In the event that a patient is withdrawn from the study, every effort will be made by the Investigator to 
document and report the reasons for withdrawal as thoroughly as possible. The reason(s) for termination 
must be clearly reported on the appropriate page of the patient’s CRF. An End-of-Treatment reason for 
discontinuation must be recorded for any patient who is randomized. If a patient is discontinued from the 
trial for any reason, every effort must be made to perform all clinical and laboratory procedures as 
scheduled for the End-of-Treatment Visit. In the event that the patient fails to return for the necessary 
visit(s), an effort must be made to contact the patient to determine the reason, and this information should 
be recorded in the appropriate source record and the end-of-treatment CRF.
5.3 Study Duration and End of Treatment
The total estimated duration of the study is up to 3 year, including 14 months to accrue patients with up to 
1 year for treatment and follow up for the last patient. Patients will be supplied study drug until they 
discontinue from the study.
End of treatment is defined when untransfused platelet count recover to > 30 x 109/L on 2 measurements 
obtained 5 days apart. For patients without platelets recovery, end of treatment will be set at 6 months. At 
that time patients will be taken off treatment and enter a long-term follow-up period for 2 years.
Subjects that completed treatment due to platelet count recover to > 30 x 109/L on 2 measurements 
obtained 5 days apart whom  developed thrombocytopenia > 30 days of end of study and fulfill the 
inclusions and exclusion criteria are allowed to be re-enrolled in the study. Subjects without platelet 
recovery that completed 6 months of treatment are not allowed to be re-enrolled in the study
5.4 Withdrawal Criteria

Patients will be discontinued from further study drug administration if any of the following occur: 
Intolerable toxicity as determined by the Investigator 

Grade 4 bleeding on either arm of this study

Development on trial of a deep venous thrombosis, pulmonary embolism or cerebrovascular 
event on either arm of this study

Grade ≥2 CPK elevation on the EACA arm

Grade  ≥3 myalgia on the EACA arm

Development on trial of disseminated intravascular coagulation (DIC)

Development on trial of a condition that requires anticoagulation 

A treatment interruption for study-drug  (EACA) related non-hematologic toxicities lasting longer 
than 28 days

Significant deviation from the protocol or eligibility criteria

Noncompliance with study or follow-up procedures

Pregnancy

Patient withdrawal of consent and decision to discontinue participation

Termination of the trial 

Any other reason that, in the opinion of the Investigator, would justify removal of the patient 
from the study
5.5 Study Termination
If the investigator, Data Monitoring Committee, or regulatory agencies discover conditions during the 
study that indicate that the study or site should be terminated, this action may be taken after appropriate 


22
consultation between the investigator, and Data Monitoring Committee. Conditions that may warrant 
termination of the study include, but are not limited to:

The discovery of a serious, unexpected, or unacceptable risk to subjects enrolled in the study

Submission of knowingly false information from the research facility to the regulatory authorities

Insufficient adherence to protocol requirements
Study termination and follow-up will be performed in compliance with the conditions set forth in the 
guidelines for GCP, International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use.
6. Safety and Quality of Life Assessments 
6.1.1 Safety Assessments: Safety will be assessed by routine physical and laboratory evaluations. AEs 
will be recorded and the severity will be graded according to the NCI CTCAE v.4.0. 
6.1.1. Adverse Events: Type, incidence, severity (graded in accordance with the NCI CTCAE v.4.0), 
timing, seriousness and relatedness, outcome, action taken with study drug, and treatment will be assessed 
and documented by the investigator continuously throughout the study. Baseline malignancy-related signs 
and symptoms will be recorded as AEs during the study if they worsen in severity or increase in 
frequency. Procedures for following AEs at the end of treatment and beyond are outlined in Section 5.1.
6.2. Quality of Life Assessments: Patients will be asked to fill the EQ-5D-5L. The EQ-5D-5L 
questionnaire is a validated, self-administered general questionnaire of health-related quality of life (HR-
QoL) issues, developed by EuroQoL Group. The questionnaire asks patients to rate their HR-QoL for 5 
dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The instrument 
contains a descriptive element, with patients being asked to rate each dimension on a 5-level descriptive 
severity scale; and a visual analog scale, where the same dimensions are rated along a 100-point visual 
ruler. Patients for whom a validated translation exists in a language in which they are fluent will complete 
the EQ-5D-5L during study visits as outlined in the Schedule of Events.
6.3.
Study Treatments:Patients will be randomized to receive for bleeding prophylaxis either EACA 
or prophylactic platelet transfusions. EACA will be self-administered by the patient on a daily schedule.
6.3.1
Dose Selection, Treatment Administration and Compliance 
6.3.1.1 EACA
The starting dose of EACA will be 1,000 mg taken orally twice daily. Patients will take the prescribed 
number of tablets at approximately the same time each day. Patients will be provided a diary card where 
the date of administration will be recorded. Patients who forget to take their dose more than 6 hours after 
it is due shall not make up the missed dose. Any missing doses should be recorded, and subsequent 
training of patients should be documented in the appropriate source record (e.g., clinic chart). The starting 
dose was selected based on our institutional experience (Section 1.3).
6.3.1.2 Prophylactic Platelet Transfusions
Patients not randomized to the EACA arm with platelet counts < 20x109/L in the out-patient or <10x109/L 
in the in-patient will receive a single donor unit of pheresed platelets in the infusion center after pre-
medication with acetaminophen and diphenhydramine per institutional guidelines. Documentation of the 
transfusion will be maintained according to the hospital’s Standard Operating Procedures, with 
documentation of the start and end time of the infusion, as well as adverse events during the infusion and 


23
its management. Platelet refractory patients will receive prophylactic platelet transfusions as described 
above.
6.3.1.3 Therapeutic Platelet Transfusions
On both arms of the study, patients will receive therapeutic platelets transfusion for any grade ≥ 2 
bleeding per standard of care. Platelet refractory patients will receive HLA match platelet transfusions per 
standard of care. 
6.3.2
Dose Escalation
Patients randomized to EACA who experience any persistent grade ≥ 2 bleeding including  hematuria,  
will receive platelet transfusions as per standard of care and have the option of increasing the dose of 
EACA to 1,000 mg three times a day. If the dose of 1,000 mg TID is poorly tolerated, then the EACA 
will be held and restarted at 1,000 mg BID after resolution of the AEs to < grade 1. 
If patient experience oral bleeding secondary to acute or chronic gingivitis or mucositis who do not 
respond to chlorhexidine 0.12% oral rinse and antibiotic treatment (including but not limited to penicillin 
and metronidazole or amoxicillin and clavulanate or ampicillin and sulbactam or clindamycin), then have 
the option of increasing the dose of EACA to 1,000 mg three times a day. If the dose of 1,000 mg TID is 
poorly tolerated, then the EACA will be held and restarted at 1,000 mg BID after resolution of the AEs to 
< grade 1. 
Patients randomized to EACA who have persistent cutaneous bruises will receive platelet transfusions as 
per standard of care and have the option of increasing the dose of EACA to 1,000 mg three times a day. If 
the dose of 1,000 mg TID is poorly tolerated, then the EACA will be held and restarted at 1,000 mg BID 
after resolution of the AEs to < grade 1. If bruising continues, patient will be taken off study.  
6.3.3
Dose Reduction
Patients randomized to EACA 1000 mg twice a day or higher who experience grade ≥2 toxicity 
attributable to EACA, will hold the study drug until resolution of the adverse event to < grade 1. EACA 
will then be reduced by 50%, restarted at 1000 mg daily after the resolution of the AE’s to < grade 1
6.4
Allocation of Treatment
The results of screening assessments for each patient will be reviewed by the study PI, who will approve 
each patient for randomization. Upon this approval, patients will be randomized to treatment with either 
EACA or standard of care prophylactic platelet transfusions using a standard randomization table. 
6.5
Concomitant Medications
All concomitant medications administered from the time of informed consent signature through 30 days 
after the end of treatment (last dose or investigator/patient decision to discontinue, whichever is later) are 
to be reported on the appropriate CRF for each patient.
6.5.1
Permitted Medications
All routine and appropriate supportive care (including red blood cell products) will be allowed during this 
study, as clinically indicated, and in accordance with the standard of care practices. Clinical judgment 
should be utilized in the treatment of any AE experienced by the patient. Information on all concomitant 
medications, administered blood products, as well as interventions occurring during the study must be 
recorded on the patient’s CRF.
6.5.2
Prohibited Medications


24
Hydroxyurea and procoagulant agents including DDAVP, recombinant FVII or prothrombin complex 
concentrate are prohibited in patients receiving EACA.
6.5.3
Treatment Supply
6.5.3.1 Formulation, Packaging and Labeling
EACA investigational drug product is supplied as tablets. Each tablet contains 500 mg of EACA active 
ingredient. Tablets will be supplied as follows: 60 count in 30 cc white high density polyethylene (HDPE) 
bottles with induction-sealed child resistant caps. Bottle labels will bear the appropriate label text as 
required by governing regulatory agencies, to include product name, product strength, number of tablets,  
lot number, appropriate temperature range for storage and statement that drug is limited by federal law to 
investigational use only.
6.5.3.2 Treatment Storage, Dispensing, and Accountability
The recommended storage condition for aminocaproic acid is 25°C. The study pharmacist or designee at 
the site will be responsible for handling, dispensing study drug, completing associated documentary 
paperwork, handling dispensing log/accountability form. Each time study medication is dispensed for a 
patient, the following information be recorded: the patient’s initials, the patient’s study number, tablet 
strength, the number of tablets dispensed with the corresponding lot number, and the initials of the person 
dispensing the drug. These logs are to be maintained by the study pharmacist in the pharmacy throughout 
the duration of the study. The Investigator is responsible for ensuring that the patient diary card(s) and 
study drug provided to the patient and returned from the patient are accounted for and noted in source 
documentation.
6.5.3.2.1
Disposition of used supplies
All used bottles or packs of study drug must be destroyed in an appropriate manner according to the 
standard practice. Destruction of such supplies will be documented. During the trial and at termination, 
patients must return all unused study drug supplies and the return of these unused study drug supplies 
must be recorded. Returned supplies must not be re-dispensed. No other utilization of EACA intended for 
use in this study will be authorized. The Principal Investigator or his/her designee will be responsible for 
the appropriate handling and disposition of residual study drug. 
7. Adverse Events Reporting
7.1
Adverse Events
7.1.1
Adverse Event Definition
An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with this 
treatment. An AE can be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product whether or not 
considered related to the medicinal product. Any worsening of a preexisting condition, which is 
temporally associated with the use of the study drug (i.e., occurs after the first dose of study drug), is also 
an AE. Adverse events include: 

Abnormal test findings 

Changes in physical exam findings

Other untoward medical events, regardless of their relationship to the study drug, such as injury, 
events that require surgery, accidents, or apparently unrelated illnesses, and hypersensitivity

AEs may include signs or symptoms resulting from: drug overdose, drug withdrawal, drug abuse, 
drug misuse, drug interactions, drug dependency, and, in utero drug exposure 


25
7.1.2
Abnormal Laboratory Tests
The criteria for determining whether an abnormal objective test finding should be reported as an AE are 
as follows:

Test result is associated with accompanying symptoms that are considered clinically significant in 
the opinion of the investigator

Test result requires additional diagnostic testing (other than merely repeating an abnormal test) or 
medical/surgical intervention

Test result leads to a change in study drug dosing or discontinuation from the study, significant 
additional concomitant drug treatment, or other therapy

Test result is considered to be an AE by the investigator 
7.1.3
Performing Adverse Event Assessment
All observed or volunteered AEs, regardless of treatment group or suspected causal relationship to the 
investigational product, will be reported as described in the following sections. For all AEs, the 
investigator must pursue and obtain information adequate to determine the outcome of the AE and to 
assess whether it meets the criteria for classification as a serious AE requiring immediate notification to 
the appropriate regulatory agencies.
7.1.4
Reporting Period
Serious Unexpected Suspected Adverse Reactions require notification of the appropriate regulatory 
agencies beginning from the time the patient provides informed consent, which is obtained prior to the 
patient’s participation in the clinical study (ie, prior to undergoing any study-related procedure and/or 
receiving investigational product), through and including 30 days after the last administration of the 
assigned study treatment or the investigator/patient decision to discontinue treatment, whichever occurs 
later. Any SAE occurring any time during the reporting period must be reported to the FDA within 15 
days of determining reportability if a causal relationship to the investigational product is suspected. Any 
SAE ongoing at the end of the reporting period should be followed as described below. For all enrolled 
patients, AEs (serious and non-serious) should be recorded on the eCRF beginning with the signing of the 
informed consent form and concluding 30 days following the last dose of the assigned study treatment or 
the investigator/patient decision to discontinue treatment, whichever occurs later. AEs ongoing after the 
reporting period: Any ongoing AEs thought to be at least possibly study-drug related and all ongoing 
SAEs after this time should be followed at least every 4 weeks until they resolve to baseline (or CTCAE 
grade ≤ 1), stabilize, or are considered to be chronic/irreversible.
7.1.5
Adverse Event Severity
The severity of AEs will be assessed according to the CTCAE, v.4.0. If the AE is not defined in the 
CTCAE, the investigator will determine the severity of the AE based on the following definitions:

Mild (grade 1): The AE is noticeable to the patient but does not interfere with routine activity. 
The AE does not require discontinuing administration or reducing the dose of the study drug

Moderate (grade 2): The AE interferes with routine activity but responds to symptomatic therapy 
or rest. The AE may require reducing the dose, but not discontinuing administration of the study 
drug

Severe (grade 3): The AE significantly limits the patient’s ability to perform routine activities 
despite symptomatic therapy. In addition, the AE leads to discontinuing administration or 
reducing the dose of the study drug

 Life-Threatening (grade 4): The AE requires discontinuing administration of the study drug. The 
patient is at immediate risk of death


26

Death (grade 5): The patient dies as a direct result of the complication or condition induced by 
administration of the study drug
7.1.6
Causality
The investigator’s assessment of causality must be provided for all AEs (serious and non-serious). An 
investigator’s causality assessment is the determination of whether exists a reasonable possibility that the 
investigational product caused or contributed to the AE. In addition, if the investigator determines an SAE 
is associated with study procedures, the investigator must record this causal relationship in the source 
documents and on the SAE form and report such an assessment in accordance with the SAE reporting 
requirements. The investigator will use medical consideration and use the following categories of 
causality to determine the relatedness of an AE with the study drug based on the following definitions. 
Not all criteria in each category of relatedness must be present.

Definitely Not Related (not drug related):  The patient did not receive study drug, OR the 
temporal sequence of the AE onset relative to the administration of the study drug is not 
reasonable, OR there is another obvious cause of the AE

Probably Not Related (not drug related): there is evidence of exposure to study drug, there is 
another more likely cause of the AE, dechallenge (if performed) is negative or ambiguous, 
rechallenge (if performed) is negative or ambiguous

Possibly Related (drug related): there is evidence of exposure to study drug, the temporal 
sequence of the AE onset relative to administration of the study drug is reasonable, the AE could 
have been due to another equally likely cause, dechallenge (if performed) is positive

Probably Related (drug related): there is evidence of exposure to study drug, the temporal 
sequence of the AE onset relative to administration of the study drug is reasonable, the AE is 
more likely explained by the study drug than by another cause

Definitely Related (drug related): there is evidence of exposure to study drug, the temporal 
sequence of the AE onset relative to administration of the study drug is reasonable, dechallenge is 
positive, rechallenge (if feasible) is positive, the AE shows a pattern consistent with previous 
knowledge of the test drug or a test drug class
7.1.7
Expectedness
The expectedness of an SAE is assessed by the Investigator in the overall classification of SAEs for 
regulatory reportability. The EACA Investigator’s Brochure will be used as the reference for 
determination of expectedness and risk assessment. 
7.2
Serious Adverse Events
The definitions and reporting requirements of ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2A, will be adhered to.
7.2.1
Serious Adverse Event Definition
An AE is considered an SAE if at least one of the following conditions applies:

Death: An AE that results in death is any patient death within 30 days of the last dose of study 
drug administration. The cause of death or AE that resulted in a fatal outcome is the SAE

Life-threatening AE: An AE that places the patient, in the view of the investigator or the sponsor, 
at immediate risk of death from the event as it occurred (i.e., this does not include an event that 
had it occurred in a more severe form might have caused death)


27

Results in a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions: Any substantial disruption of a person’s ability to conduct normal life 
functions

Inpatient hospitalization or prolongation of existing hospitalization: Hospitalization refers to 
admission of a patient into a hospital for any length of time

A congenital anomaly/birth defect: A fixed, permanent impairment established at or before birth

Cancer: Occurrence or diagnosis of a new cancer during the study is considered an SAE. A new 
cancer is a cancer that is histopathologically different than the cancer under study in the trial (ie, 
does not include metastatic or progressive disease)

Overdose: Occurrences of overdose must be reported as an SAE

Important medical event: Medical and scientific judgment should be exercised in determining 
whether an event is an important medical event. An important medical event may not result in 
death, be life-threatening, or require hospitalization. However, if it is determined that the event 
may jeopardize the patient and/or may require intervention to prevent one of the other outcomes 
listed in the definition above, the important medical events should be reported as serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization; or the 
development of drug dependency or drug abuse.
Adverse events (reported from clinical studies) that require hospitalization or prolongation of 
hospitalization are considered serious. Any initial admission (even if less than 24 hours) to a health care 
facility meets these criteria. Adverse events that require emergency room care that do not result in 
hospital admission are not SAEs unless assessed by the investigator to be an important medical event. 
Hospitalization does not include the following: Hospice facilities, Respite care, skilled nursing facilities, 
Nursing home, Routine emergency room admissions, and same day surgeries (as outpatient/same 
day/ambulatory procedure)
Hospitalization or prolongation of hospitalization in the absence of a precipitating AE is not in itself an 
SAE. Examples include: Social admission (eg, patient has no place to sleep), Protocol-specified 
admission during a clinical study (eg, for a procedure required by the study protocol), Optional admission 
not associated with a precipitating AE (eg, for elective cosmetic surgery that was planned prior to study 
enrollment [appropriate documentation is required for these cases]), Hospitalization or prolongation of 
hospitalization for scheduled therapy of  target malignancy of the study is not considered an SAE
7.2.2
Reporting Serious Adverse Events
The investigator or designee must

Complete a Serious Adverse Event Case Report Form in the subject’s study record within 72 
hours of recognition.  

Submit events that are a Serious Unexpected Suspected Adverse Reaction to the FDA within 15 
calendar days of determining reportablility

Observe Emory University IRB Unanticipated Problem policy to determine events that meet 
requirements for immediate reporting. If an event meets the Emory University IRB requirements 
as an UP, the event will be submitted to the IRB and the DSMB. This timeframe also applies to 
additional new information (follow-up) on previously forwarded SAEs. Should the FDA or 


28
national regulatory authorities require additional data on the event; the sponsor-investigator will 
ensure that those data are provided to the appropriate regulatory agencies in a timely fashion.
The following information about the patient and the event will need to be collected and available:

Investigator identification

Patient identification code (eg, sex, age, or date of birth)

Information on study drug (eg, start/stop date, dose and frequency of study drug administered)

Description of event
In addition to the above information, the sponsor will require the investigator’s assessment of the 
following:

Severity of the SAE

Relationship of the SAE to the study drug

Outcome of the SAE
7.2.3
Follow-up Information of Serious Adverse Events
Appropriate diagnostic tests should be performed and therapeutic measures, as medically indicated, 
should be instituted. Appropriate consultation and follow-up evaluations should be carried out until the 
event has resolved or is otherwise explained by the investigator. For all SAEs, the investigator is 
obligated to pursue and provide information to the appropriate regulatory agencies. There should be 
routine follow-up through and including 30 days after the last administration of assigned study treatment 
or the investigator/patient decision to discontinue treatment, whichever occurs later, in all patients in 
order to monitor for the occurrence of SAEs. If an SAE continues after the 30-day evaluation period, then 
the patient must be followed until the event resolves or returns to baseline. The medical monitor may 
specify a longer period of time if required to assure the safety of the patient.
7.3
Other Safety Issues
7.3.1
Pregnancy
Females of childbearing potential and fertile males will be informed as to the potential risk of conception 
while participating in this study and will be advised that they must use effective contraception from 
randomization through at least 30 days after the end of treatment. A pregnancy test will be performed on 
each pre-menopausal female of childbearing potential immediately prior to randomization, and again at 
the End-of-Treatment Visit. A negative pregnancy test must be documented prior to administration of 
study drug. If a patient is confirmed pregnant during the trial, study drug administration must be 
discontinued immediately. The investigator must immediately notify the appropriate regulatory agencies 
of this event and record the pregnancy on a Pregnancy Form. The investigator must immediately report 
follow-up information to the appropriate regulatory agencies regarding the course of the pregnancy, 
including perinatal and neonatal outcome, regardless of whether the patient has discontinued participation 
in the study. If the pregnancy results in the birth of a child, additional follow-up information may be 
requested. If the pregnancy results in spontaneous abortion or stillbirth, the event should be reported as an 
SAE. Pregnancy outcomes must be collected for the female partners of any males who took study drug in 
this study. Consent to report information regarding these pregnancy outcomes should be obtained from 
the female partner.
7.3.2
Overdose 


29
An overdose is defined as the accidental or intentional ingestion or infusing of any dose of a product that 
is considered BOTH excessive AND medically important. All occurrences of overdose must be reported 
as an SAE. Monitor adverse events as instructed in the schedule of events and as clinically indicated.
7.4 Unanticipated Problems 
Unanticipated problems (UPs) are events (adverse events or not) that will be assessed by the PI as 
unexpected, related to study participation, and involving risk for participants or others.  A reportable 
event that fulfills all of these characteristics is considered an unanticipated problem.
To be unanticipated, the event should be unexpected, not described in the study documents, or if 
described before, it is now presenting with increased severity, duration, or frequency.
To be related to study participation, the event should be probably or possibly related to study 
participation, due to drug, or as a consequence of a study procedure (even if the procedure is considered 
standard of care).  If an event could be explained by the underlying medical condition, it is not considered 
related.
To involve risk for participants or others, the event may affect subjects’ risk.  Even if the event did not 
result in harm, if the subject could have been affected by the event (safety, rights, welfare), the event is 
reportable.
Unanticipated problems  will be  report to the IRB using the reportable events form within 10 calendar 
days from the date the PI first learn about the event if the problem was unanticipated, related and 
involving risk to participants or others or if happening at increase frequency, duration or intensity that 
previously anticipated.
8. Statistical Considerations
8.1
General Considerations
For the purposes of this protocol and all analyses, a month of treatment is defined as 28 days, and will be 
the same length as a cycle of treatment for both groups. 
8.2
Analysis Population
Intention to treat (ITT) population: The ITT population includes all patients who are randomized to the 
study. Patients will be analyzed according to the treatment to which they were assigned. 
Safety Population: The safety population includes all patients who have received at least 1 dose of EACA. 
Patients included in the safety population will be analyzed according to the treatment they received.
Per-protocol Population: The per-protocol population includes all patients who are randomized, receive at 
least one dose of study drug, and have no major protocol violations that could be expected to impact 
response data, such as: failure to satisfy one or more eligibility criteria, administration of other anti-cancer 
therapy concurrent with study drug, and administration of incorrect study drug doses. Major protocol 
violations will be finalized and documented prior to final data analysis.
8.3
Study Endpoints
8.3.1
Primary Endpoint
The primary objective of this study is to compare at the end of the study, the proportion of patients with 
major bleeding during the study period among patients randomized to receive either EACA or standard of 
care prophylactic platelet transfusions.


30
8.3.2
Secondary Endpoint
Secondary endpoints include:

proportion of patients with any bleeding during the study period in each arm

the total number of units of platelets transfused in each arm at the end of the study

Quality of life as measured by  in each arm before the study and at the end of the study

Safety in each arm
8.4
Determination of Sample Size 
This randomized, open-label phase II study is designed to compare proportion of patient with bleedings 
noted during the study. Patients will be assigned to receive prophylactic EACA (experimental arm) or 
prophylactic platelet (standard of care) in a 1:1 fashion. Previous studies suggest that the proportions of 
patients with major bleeding will be expected to be 8% and 30% in experimental arm and standard of care 
arm, respectively. With one sided Fisher’s exact test, the sample size of 45 patients in each arm will 
achieve a power of 80% at the significance level of 5% to test whether prophylactic EACA can prevent 
major bleeding better than the standard of care. After adjusting for a 10% drop out rate, the actual 
required sample size will be 50 patients per arm. Therefore, the total sample size of the study will be 100 
patients. 
8.5
Efficacy Analysis
8.5.1
Definition of Efficacy Endpoints
The primary, key secondary and other secondary efficacy endpoints are listed in Section 3.2 and 3.3. This 
section defines the endpoints themselves and the associated conditions defining loss of those endpoints.
8.5.2
Primary Endpoint Analysis
The primary analysis of the primary endpoint will be performed using a one-sided fisher exact test to 
compare the proportions of patients with major bleeding during the whole study between the two arms. 
The significance level is set at 0.05. This primary analysis will be based on the ITT population.
8.5.3
Secondary Endpoint Analysis
One-sided t-test will be used to compare the total number of bleeding episodes noted during the study 
between the two arms. Two-sided t-test will be employed to compare the total number of units of platelets 
transfused at the end of the study between the two arms. Appropriate statistical tests (Chi-square test, t-
test, Wilcoxon’s rank sum test, etc.) will be conducted to compare the each score of the quality of life 
between the two arms before the study and at the end of the study, respectively. The change of each score 
of the quality of life from before the study to the end of the study will also be compared between the two 
arms. The safety in each arm will be also compared with Fisher’s exact test. The analyses of secondary 
endpoints will be performed on the ITT population and the significance level will be kept at 0.05 for all 
tests.
For the primary and secondary efficacy endpoints, subgroup analyses will be performed by baseline 
potential prognostic factors. Subgroups will include: age, gender, race, underlying diagnosis, and other 
disease-related prognostic factors (disease status).
8.6
Safety Analysis
All patients receiving at least 1 dose of study drug will be considered evaluable for safety. Patients will be 
analyzed for safety according to the treatment which they received. Listings of laboratory test results will 


31
also be generated, and descriptive statistics summarizing the changes in laboratory tests over time will be 
presented. Exposure to study drug over time will also be summarized. The AE incidence rates, as well as 
the frequency of occurrence of overall toxicity, categorized by toxicity grades (severity) will be described 
for each treatment arm and be compared between two arms using two-sided Chi-square test or t-test.
8.7
Quality of Life Analysis
Quality of life and health outcomes measures are being collected using the EQ-5D-5L instruments before 
the study and at the end of the study. Means and medians of raw scores of these questionnaires will be 
summarized for each treatment group for each domain and be compared between the two arms with t-test 
or Wilcoxon ranks sum test.
8.8
Interim Analysis
Three interim analyses are planned after 11 patients in each arm have been randomized and their results 
have been obtained. Each interim analysis will focus on the primary endpoint, the proportion of patients 
with major bleeding ever noted during the study. To maintain an overall Type I error rate of 0.05 (1-
sided), an O’Brien Fleming approach will be used which requires a 1-sided p-value < 0.001 at the first 
interim analysis (at 25% of total sample size). If this boundary is not crossed, then the study will continue 
and the second interim analysis will be conducted at 50% of the total sample side which requires a 1-sided 
significance level of 0.004. If this boundary is not crossed at the second interim analysis then, the study 
will continue and a third interim analysis will be conducted at 75% of the total sample side which requires 
a 1-sided significance level of 0.019. If this boundary is not crossed, the final primary analysis will be 
performed after completing 100% of the sample size using a 0.043 one-sided significance level.
8.8.1
Impact on Conduct of Study
It is expected that the study will be fully enrolled prior to the conduct of the interim analysis. In the event 
that the study crosses the boundary at the interim analysis we would expect to continue patients on their 
randomized treatment arm to allow for continued assessment of other time points and the secondary 
endpoints. 
8.9
Protocol Deviations and Violations
To be protocol-compliant, a patient must not have any major protocol deviations during the study period. 
Protocol deviations will be identified prior to final analysis and will be listed by treatment group in the 
clinical study report.
9.0
Quality Control and Quality Assurance and Study Monitoring
The investigator will be responsible for performing quality control and assurance checks. Before enrolling 
any patients into this study, the investigator will review the protocol, the CRFs and instructions for their 
completion, the procedure for obtaining informed consent, and the procedure for reporting AEs with all 
personnel listed on the delegation of authority and FDA1572. The investigator will perform monthly 
evaluation of the conduct of the trial and perform the following:

Review information recorded in the CRFs and verify against source documents

Review data for safety information and to identify missing data  

Review protocol violations, out-of-range data, and other data inconsistencies
This study will be also be monitored by the DSMB Winship Committee that will address the following: 

Adherence to the protocol (the investigator should document and explain any deviation from the 
approved protocol)


32

The completeness and accuracy of the CRFs and the dispensing and inventory record (adequate 
time and space for these visits should be allocated by the investigator)

Compliance with regulations (the verification will require comparison of the source documents to 
the CRFs)
10. Ethical Conduct of the Study
This study will be conducted in accordance with the ethical standards that have their origin in the 
Declaration of Helsinki and that are consistent with GCP guidelines and the applicable regulatory 
requirements.
10.1
Institutional Review Boards Approval
The protocol and the informed consent document must have the initial and continuing review approval of 
the IRB. The signed IRB approval letter must identify the documents approved (ie, list the investigator’s 
name, the protocol number and title, the date of the protocol and informed consent document, and the date 
of approval of the protocol and the informed consent document). Any advertisements used to recruit 
patients should also be reviewed by the IRB. 
10.2
Patient Information and Consent
The study informed consent form will follow regulations that provide protection for human patients in 
clinical investigations and to describe the general requirements for informed consent. The informed 
consent document will contain all of the elements of the informed consent specified in the regulations. 
Nothing in this protocol or the regulations is intended to limit the authority of a physician to provide 
emergency medical care under applicable regulations. In addition, the investigator should be aware that 
some regulations require that he/she permit regulatory agencies to conduct inspections and review records 
pertaining to this clinical investigation.
10.3
Patient Confidentiality
Throughout the course of the study, all PHI record will be kept securely using password protected 
computer terminals. Access to the data will be on a need to know basis, therefore, only those investigators 
listed in the protocol will have access to the data. A high premium will be placed on ensuring that 
identifying information is not made available to staff engaged in routine care of the patient unless if 
necessary for the safe performance of their duties. For this reason, all research-related samples and 
clinical data will be de-identified using assigned study-specific registration numbers for such non-SOC 
procedures as much as possible.
The investigator agrees to keep all information in strict confidence and to request similar confidentiality 
from his/her staff and the IRB/IEC/REB. Study documents (investigators' brochures and other material) 
will be stored appropriately to ensure their confidentiality. The information provided to the investigator 
may not be disclosed to others without direct written authorization, except to the extent necessary to 
obtain informed consent from patients who wish to participate in the trial. 
10.4
Data Safety Monitoring Committee
Patient safety, study efficacy and compliance will be reviewed at the Hematology working group meeting. 
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute will also oversee 
the conduct of this study (every 6 months or annually – depending on the risk level of the protocol). This 
committee will review pertinent aspects of study conduct including patient safety, compliance with 
protocol, data collection and efficacy. The committee will review the charts of 10% of patients enrolled to 
the study and two of the first 5 patients entered to the study. The Committee reserves the right to conduct 


33
additional audits if necessary. The Principal Investigator (PI) or designee is responsible for notifying the 
DSMC about the accrual of patients when the first 5 have been entered to the study. The PI or designee 
will also notify the DSMC of study status within 2 months before the next scheduled review is due.
11. Data Handling and Record Keeping
11.1
Case Report Forms and Study Records
Study-specific CRFs will be made available for the conduct of this study. Study data, contained in source 
documentation, will be entered into the CRFs for all patients enrolled in the study. All pertinent data 
records will be maintained on site for 5 years after completion or termination of the study.
11.2
Source Documents
The investigator agrees that regulatory agencies will have the right, both during and after this study, to 
conduct inspections and to audit and review medical records pertinent to the clinical study as permitted by 
the regulations. Patients will not be identified by name in any reports stemming from the study, and 
confidentiality of information in medical records will be preserved. The confidentiality of the patient will 
be maintained unless disclosure is required by regulations. 
11.3
Retention of Data
Trial documents (including correspondence related to this clinical study, patient records, source 
documents, CRFs, study drug inventory records and IRB and sponsor correspondence pertaining to the 
study, original patient, laboratory, and study drug inventory records relating to the study) will be retained 
until 5 years after completion or termination of the study. Thereafter, records will not be destroyed but 
stored at an off-site location according to Emory policy.
 
11.4
Study Termination
The study will be terminated at any time for any of the following reasons:

Failure to enroll patients

Protocol violations

Inaccurate or incomplete data

Unsafe or unethical practices

Questionable safety of the study drug

Suspected lack of efficacy of the study drug

Administrative decision
In the event of the termination of the Study, a written statement describing why the study was terminated 
prematurely will be made available by the investigator
12. References 
1.
Heddle, NM, A descriptive analysis of international transfusion practice and bleeding outcomes 
in patients with acute leukemia, Transfusion 2006; 46:903-911
2.
Gernsheimer, TB Platelet transfusion in the 21st century, ISBT 2011;6: 245-248


34
3.
Paolo Rebulla, M.D., Guido Finazzi, M.D., Francesca Marangoni, M.D., Giuseppe Avvisati, 
M.D., Luigi Gugliotta, M.D., Gianni Tognoni, M.D., Tiziano Barbui, M.D., Franco Mandelli, 
M.D., and Girolamo Sirchia, M.D. for the Gruppo Italiano Malattie Ematologiche Maligne 
dell'Adulto N Engl J Med 1997; 337:1870-187
4.
Heckman KD, Weiner GJ, Davis CS, Strauss RG, Jones MP, Burns CP. Randomized study of 
prophylactic platelet transfusion threshold during induction therapy for adult acute leukemia: 
10,000/μL versus 20,000/μL. J Clin Oncol 1997;15:1143-1149
5.
Schiffer, CA et al. Platelet transfusion for patient with cancer, JCO 2001;19:1519
6.
Klingemann, H.G Refractoriness to random donor platelet transfusions in patients with aplastic 
anemia: a multivariate analysis of data from 264 cases. British Journal of 1987 Haematology; 66: 
115–121.
7.
Legler, T.J Frequency and causes of refractoriness in multiply transfused patients. Annals of 
Hematology 1997; 74: 185–189.
8.
Nevo, S Acute bleeding and thrombocytopenia after bone marrow transplantation. Bone Marrow 
Transplantation 2001; 27: 65–72.
9.
European Medicines Agency. Antifibrinolytic medicine (aminocaproic acid), article 31. 2012.
Appendix 1
WHO grade
Description
0
No bleeding
1
Only petechial bleeding
Including retinal bleeding without visual impairment
2
Mild blood loss
Including melena, hematuria, hematemesis and hemoptysis
3
Gross blood loss
Including any bleeding requiring red cell transfusion
4
Debilitating blood loss
Including retinal and cerebral bleeding with high morbidity or fatal outcome