Traumatic Injury Clinical Trial Evaluating Tranexamic Acid in Children (TIC-TOC): A Pilot and Feasibility Study
Phase: PHASE2
Conditions: Brain Injuries, Wounds and Injuries, Hemorrhage
Sponsor: Daniel Nishijima, MD, MAS

Traumatic Injury Clinical Trial Evaluating
Tranexamic Acid in Children (TIC-TOC): A Pilot
and Feasibility Study
(TIC-TOC Trial)
PECARN Protocol Number 036
Pediatric Emergency Care Applied Research Network
National Heart, Lung, and Blood Institute (NHLBI)
Protocol Version 2.03
Version Date: October 24, 2018
Printing Date: October 24, 2018

Copyright c⃝2016 - 2017. University of Utah School of Medicine on behalf of the
Principal Investigators, Daniel K. Nishijima, MD, MAS; Nathan Kuppermann, MD, MPH
and the Pediatric Emergency Care Applied Research Network (PECARN). All rights
reserved.
This protocol is PECARN Protocol Number 036, and has been authored by Daniel K.
Nishijima, MD, MAS; Nathan Kuppermann, MD, MPH, University of California, Davis
Health, Sacramento, for implementation with the PECARN investigators. This study
is supported by 1R34HL135214-01 awarded to University of California, Davis Health,
Sacramento (PIs: Daniel K. Nishijima, MD, MAS; Nathan Kuppermann, MD, MPH) by
the National Heart, Lung, and Blood Institute.
The PECARN Research Node Centers are the Nationwide Children’s Hospital, Cincin-
nati Children’s Hospital Medical Center, Columbia University, University of California at
Davis Health, Sacramento, University of Arizona Health Science Center, and Children’s
National Medical Center are supported by Cooperative Agreements U03-MC00003, U03-
MC22684, U03-MC00007, U03-MC00001, U03-MC28845, and U03-MC00006 from the
Emergency Medical Services for Children (EMSC) Program, Maternal and Child Health
Bureau, Health Resources and Services Administration.
This document was prepared by the PECARN Data Coordinating Center (DCC)
located at the University of Utah School of Medicine, Salt Lake City, Utah. The document
was written and typeset using LATEX2ε. The DCC at the University of Utah is supported
by Cooperative Agreement U03-MC00008 from the Emergency Medical Services for
Children (EMSC) Program, Maternal and Child Health Bureau, Health Resources and
Services Administration.

Protocol 036 (Nishijima, Kuppermann)
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PROTOCOL TITLE:
Traumatic Injury Clinical Trial Evaluating Tranexamic Acid in Children (TIC-TOC): A
Pilot and Feasibility Study
Short Title: TIC-TOC Trial
PECARN Protocol Number: 036
Lead Investigators and Authors:
Daniel K. Nishijima, MD, MAS; Nathan Kuppermann, MD, MPH
University of California, Davis Health, Sacramento
Protocol Version: 2.03
Version Date: October 24, 2018
I conﬁrm that I have read this protocol, I understand it, and I will conduct the study
according to the protocol. I will also work consistently with the ethical principles that have
their origin in the Declaration of Helsinki and will adhere to the Ethical and Regulatory
Considerations as stated. I conﬁrm that if I or any of my staﬀare members of the Insti-
tutional Review Board, we will abstain from voting on this protocol, its future renewals,
and its future amendments.
Principal Investigator Name:
Principal Investigator Signature:
Date:
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Contents
1
Study Summary
9
1.1
Study Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
1.2
Outcome Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
1.3
Subject Eligibility, Accrual and Study Duration . . . . . . . . . . . . . .
11
1.3.1
Inclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
1.3.2
Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
2
Rationale and Background
15
2.1
Traumatic coagulopathy and hyperﬁbrinolysis increases morbidity and
mortality after pediatric trauma . . . . . . . . . . . . . . . . . . . . . . .
15
2.2
Targeting ﬁbrinolysis may attenuate post-traumatic hemorrhage and de-
crease blood product transfusion requirements . . . . . . . . . . . . . . .
16
2.3
TXA has not been appropriately studied in children with hemorrhagic
injuries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17
3
Study Design and Data Collection
17
3.1
Study Design Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17
3.2
Participant Screening and Consent
. . . . . . . . . . . . . . . . . . . . .
18
3.2.1
Missed Eligible Subjects . . . . . . . . . . . . . . . . . . . . . . .
18
3.3
Baseline Data Collection . . . . . . . . . . . . . . . . . . . . . . . . . . .
18
3.3.1
Biomarker testing . . . . . . . . . . . . . . . . . . . . . . . . . . .
19
3.4
Data Collection During Hospitalization . . . . . . . . . . . . . . . . . . .
21
3.4.1
TXA levels
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22
3.4.2
GCS score assessment and pupillary examination
. . . . . . . . .
22
3.4.3
Blood product transfusion volume . . . . . . . . . . . . . . . . . .
22
3.4.4
Hospital discharge information . . . . . . . . . . . . . . . . . . . .
22
3.5
Follow Up Data Collection . . . . . . . . . . . . . . . . . . . . . . . . . .
24
3.5.1
Pediatric Quality of Life (PedsQL), Pediatric GOS-E, and digit
span evaluations
. . . . . . . . . . . . . . . . . . . . . . . . . . .
24
3.6
General Management Principles . . . . . . . . . . . . . . . . . . . . . . .
24
4
Study Procedures
24
4.1
Randomization (Enrollment) . . . . . . . . . . . . . . . . . . . . . . . . .
24
4.2
Study Drug Administration
. . . . . . . . . . . . . . . . . . . . . . . . .
26
4.2.1
Rationale for Study Doses . . . . . . . . . . . . . . . . . . . . . .
26
4.2.2
Manufacturing and Distribution of the Study Drug
. . . . . . . .
28
4.2.3
Study Drug Administration
. . . . . . . . . . . . . . . . . . . . .
29
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4.2.4
Discontinuation of Study Drug . . . . . . . . . . . . . . . . . . . .
30
4.3
Blinding and Unblinding . . . . . . . . . . . . . . . . . . . . . . . . . . .
30
5
Data Analysis
34
5.1
Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
34
5.1.1
Blood Transfusion
. . . . . . . . . . . . . . . . . . . . . . . . . .
35
5.1.2
Intracranial Hemorrhage Progression at 24 hours (plus or minus 6
hours) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
35
5.1.3
PedsQL
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
36
5.1.4
Glasgow Outcome Score Extended (GOS-E) Peds . . . . . . . . .
36
5.1.5
Digit Span Recall Test (working memory)
. . . . . . . . . . . . .
37
5.1.6
Biomarkers
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
37
5.1.7
Safety Outcomes
. . . . . . . . . . . . . . . . . . . . . . . . . . .
37
5.2
Randomization and Stratiﬁcation . . . . . . . . . . . . . . . . . . . . . .
38
6
Data Management
39
6.1
Clinical Site Data Management
. . . . . . . . . . . . . . . . . . . . . . .
39
6.2
Electronic Data Capture System . . . . . . . . . . . . . . . . . . . . . . .
39
6.3
Study Monitoring
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
39
6.3.1
Site Monitoring Plan . . . . . . . . . . . . . . . . . . . . . . . . .
39
6.3.2
Clinical Site Monitoring
. . . . . . . . . . . . . . . . . . . . . . .
40
6.3.3
Remote Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . .
40
6.3.4
Pharmacy Monitoring
. . . . . . . . . . . . . . . . . . . . . . . .
40
6.4
Data Coordinating Center . . . . . . . . . . . . . . . . . . . . . . . . . .
40
6.4.1
Data Center Description . . . . . . . . . . . . . . . . . . . . . . .
40
6.4.2
Security and Conﬁdentiality . . . . . . . . . . . . . . . . . . . . .
42
6.5
Record Access . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
43
7
Protection of Human Subjects
43
7.1
Institutional Review Board (IRB) Approval
. . . . . . . . . . . . . . . .
43
7.1.1
Reporting of IRB Actions
. . . . . . . . . . . . . . . . . . . . . .
44
7.2
Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
44
7.3
Exception from Informed Consent (EFIC)
. . . . . . . . . . . . . . . . .
46
7.4
Waiver of Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . .
51
7.5
Potential Risks
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
52
7.6
Protections Against Potential Risks . . . . . . . . . . . . . . . . . . . . .
54
7.7
Potential Beneﬁts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
55
7.8
Withdrawal from Study
. . . . . . . . . . . . . . . . . . . . . . . . . . .
55
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8
Data and Safety Monitoring Plan
55
8.1
Data Safety Monitoring Board (DSMB) . . . . . . . . . . . . . . . . . . .
55
8.2
Frequency of Interim Analysis . . . . . . . . . . . . . . . . . . . . . . . .
56
8.3
Conﬂict of Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
56
8.4
Adverse Event Reporting . . . . . . . . . . . . . . . . . . . . . . . . . . .
57
8.4.1
Deﬁnitions, Relatedness, Severity and Expectedness . . . . . . . .
57
8.4.2
Time Period for Adverse Events . . . . . . . . . . . . . . . . . . .
59
8.4.3
Data Collection Procedures for Adverse Events
. . . . . . . . . .
59
8.4.4
Unanticipated Problems (UP) . . . . . . . . . . . . . . . . . . . .
60
8.4.5
Monitoring Serious Adverse Events . . . . . . . . . . . . . . . . .
60
8.4.6
Follow-up of Serious, Unexpected and Related Adverse Events . .
61
9
Study Training
61
9.1
Study Training
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
61
9.2
PECARN Network Involvement . . . . . . . . . . . . . . . . . . . . . . .
62
10 Regulatory Issues
63
10.1 Food and Drug Administration
. . . . . . . . . . . . . . . . . . . . . . .
63
10.2 Health Insurance Portability and Accountability Act
. . . . . . . . . . .
63
10.3 Inclusion of Women and Minorities . . . . . . . . . . . . . . . . . . . . .
63
10.4 ClinicalTrials.gov Requirements . . . . . . . . . . . . . . . . . . . . . . .
63
10.5 Retention of Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
64
Bibliography
64
List of Figures
1
Schema of Study Objectives . . . . . . . . . . . . . . . . . . . . . . . . .
10
2
Flow diagram of blood draws for biomarker testing and TXA levels
. . .
20
3
TEG parameters
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
4
Schedule of Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . .
23
5
Plasma concentrations of TXA by dosing (Adapted from Koster et al.47).
27
6
Weight-Based Dosing for All Arms
. . . . . . . . . . . . . . . . . . . . .
31
7
Weight-Based Dosing of TXA Dose A and TXA Dose B . . . . . . . . . .
32
8
Study Flow Chart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33
9
Outcome Determination
. . . . . . . . . . . . . . . . . . . . . . . . . . .
34
10
Block Randomization . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
38
11
Informed Consent Procedures
. . . . . . . . . . . . . . . . . . . . . . . .
45
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12
Parent/guardian present and reasonable time to obtain informed consent
46
13
Parent/guardian absent or unable to provide informed consent . . . . . .
48
14
Parent/guardian present but not suﬃcient time to obtain informed consent 49
15
Mortality by time to treatment
. . . . . . . . . . . . . . . . . . . . . . .
52
16
Eﬀect of 1 hour delay in start of treatment with TXA on proportion of
patients who will beneﬁt and on risk of death
. . . . . . . . . . . . . . .
53
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1
Study Summary
This study is a Phase II, multi-center, randomized, double-blinded, placebo-controlled
trial. It is a parallel arms design pilot trial randomizing 40 subjects.
1.1
Study Objectives
The primary objective of this pilot study is to collect preliminary data on the safety and
eﬃcacy of TXA in severely injured children. We will also assess the overall feasibility
to potentially conduct a large, multi-center, clinical trial evaluating the beneﬁt of TXA
in children with signiﬁcant hemorrhagic injuries. We will randomize subjects to one of
three arms: 1) TXA dose A (low), 2) TXA dose B (high), or 3) placebo. (Figure 1 on the
following page).
Speciﬁcally, the study objectives of this pilot and feasibility study are to:
• Provide preliminary data on the safety and eﬃcacy of TXA in severely injured
children with torso and/or head injuries;
• Evaluate the ability to eﬃciently screen, identify, consent, randomize, and initiate
study intervention within 3 hours of injury;
• Demonstrate the ability to measure and complete 48-hour (blood product transfusion
requirements) and early and long-term (global neurocognitive functioning) outcomes;
• Evaluate the proportion of subjects with the outcomes of interest with the current
inclusion/exclusion criteria;
• Assess protocol adherence and variability of care in randomized subjects; and
• Identify operational eﬃciencies and ineﬃciencies with the potential to enhance the
success of the subsequent clinical trial
1.2
Outcome Measures
This pilot study is not powered for a conﬁrmatory test of eﬃcacy or safety of TXA. To
provide preliminary data on safety and eﬃcacy and to evaluate our ability to reliably
determine clinical outcomes, we will collect the following data in this pilot trial:
1. The total amount of blood products transfused (packed red blood cells, plasma,
platelets, and cryoprecipitate in mL/kg) in the initial 48 hours following randomiza-
tion,
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Figure 1: Schema of Study Objectives
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2. Intracranial hemorrhage progression at 24 hours (plus or minus 6 hours),
3. Global functioning, speciﬁcally Pediatric Quality of Life (PedsQL) and Pediatric
Glasgow Outcome Scale Extended (GOS-E Peds) scores at 1 week, 1 month, 3
months, and 6 months,
4. Short term memory (digit span test),
5. Adverse events, speciﬁcally thromboembolic (TE) events and seizures.
1.3
Subject Eligibility, Accrual and Study Duration
Children younger than 18 years with evidence of hemorrhagic injuries to the torso or brain
will be eligible. Eligible subjects will be divided into three groups (head injury, torso
injury, or head and torso injury) based on inclusion criteria below. Subjects in the com-
bined head and torso injury group must meet entry criteria for both head and torso trauma.
1.3.1
Inclusion Criteria
Inclusion criteria are:
1. Less than 18 years old AND
Penetrating Torso Trauma:
2. Penetrating trauma to the chest, abdomen, neck, pelvis, or thigh with at least one
of the following:
• age-adjusted hypotension, or
• age-adjusted tachycardia despite adequate resuscitation ﬂuids, or
• radiographic evidence of internal hemorrhage, or
• clinical suspicion of ongoing internal hemorrhage, OR
Blunt Torso Trauma:
3. Clinical suspicion of hemorrhagic blunt torso injury and at least one of the following:
• age-adjusted hypotension, or
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• persistent age-adjusted tachycardia despite adequate resuscitation ﬂuids, OR
4. Hemothorax on chest tube placement or imaging; OR
5. Clinical suspicion of hemorrhagic blunt torso injury and intraperitoneal ﬂuid on
abdominal ultrasonography (Focused Assessment with Sonography in Trauma;
FAST); OR
6. Intra-abdominal injury on CT with either contrast extravasation or more than trace
intraperitoneal ﬂuid; OR
7. Pelvic fracture with contrast extravasation or hematoma on abdominal/pelvic CT
scan with at least one of the following:
• age-adjusted tachycardia or
• age-adjusted hypotension, OR
Head Trauma:
8. GCS score less than or equal to 13 with associated intracranial hemorrhage on
cranial CT scan (enroll after CT scan)
Determination of age
Patients younger than 18 years at the time of enrollment are eligible for the study. Age
will be determined from the patient, relative, friend or the EMS personnel. In cases where
age is not known, an estimation of age by the treating clinician will be used to determine
eligibility.
Determination of time of injury
Time of injury may be provided by the subject, relative, friend, witness, EMS personnel,
or any other treating provider. An estimation of the time of injury is acceptable. If
conﬂicting reports on the time of injury exist, the time that may be viewed as the most
reliable will be used. If the time of injury is unknown, the subject is not eligible for
enrollment. Patients are excluded if the ﬁrst dose of the study drug will be unable to be
administered within 3 hours of the traumatic event.
Age-adjusted hypotension
This will be determined by accepted guidelines for vital signs in children.
Penetrating trauma
This will include stab wounds, gunshot wounds, or other objects that have penetrated
the dermis.
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Intra-abdominal injury
This will include any injury to the spleen, liver, kidney, gastrointestinal tract, or intraab-
dominal vessels.
Intraperitoneal ﬂuid on abdominal ultrasound
This is deﬁned as any ﬂuid identiﬁed in the right upper quadrant (Morisons pouch), left
upper quadrant or pelvis on the FAST examination.
Glasgow Coma Scale (GCS score)
Patients with GCS scores less than or equal to 13 and evidence of intracranial hemor-
rhage on cranial CT scan will be eligible for enrollment. The GCS scoring scale has a
high sensitivity and excellent inter-rater reliability among physicians of multiple disci-
plines and nursing staﬀ.1, 2 In subjects who are preverbal (younger than 2 years), we
will use the pediatric GCS score.3 In subjects who are intubated and a verbal score
cannot be assessed, we will use a predicted verbal score that has been previously validated.4
Intracranial hemorrhage on initial cranial CT
This will include any of the following ﬁndings: subdural hematoma, intraventricular hem-
orrhage, or intraparenchymal (cerebral) hematoma/hemorrhage/contusion. Intracranial
hemorrhage can be due to either blunt or penetrating trauma.
1.3.2
Exclusion Criteria
Exclusion criteria include any of the below:
1. Unable to administer study drug within 3 hours of traumatic event
2. Known pregnancy
3. Known prisoners
4. Known wards of the state
5. Cardiac arrest prior to randomization
6. GCS score of 3 with bilateral unresponsive pupils
7. Isolated subarachnoid hemorrhage, epidural hematoma, or diﬀuse axonal injury
8. Known bleeding/clotting disorders
9. Known seizure disorders
10. Known history of severe renal impairment
11. Unknown time of injury
12. Previous enrollment into the TIC-TOC trial
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13. Prior TXA for current injury
14. Non-English and non-Spanish speaking
15. Known venous or arterial thrombosis
Known pregnancy
This will be identiﬁed by history, physical examination or positive pregnancy test (if
done prior to randomization) in females of child-bearing age. TXA is FDA pregnancy
category B (Animal reproduction studies have failed to demonstrate a risk to the fetus and
there are no adequate and well-controlled studies in pregnant women). Given the overall
safety proﬁle of TXA in pregnancy, we will not mandate checking pregnancy testing
prior to enrollment but will stop study drug if pregnancy is identiﬁed. Prior studies of
TXA use in pregnancy have demonstrated no increase in thromboembolic complications.5–7
Known prisoners
This will be identiﬁed by police or prison guards with patient.
Known wards of the state
These patients will be excluded per federal regulations (21 CFR 50.56).
Cardiac arrest
This will be deﬁned as loss of pulses requiring chest compressions prior to randomization.
Patients believed to have inappropriately received chest compression (in the presence of
cardiac activity) are still eligible.
GCS score of 3 with bilateral non-reactive pupils
Our pilot data suggests that these patients have a mortality rate close to 100% and thus
are unlikely to beneﬁt from TXA.
Isolated subarachnoid hemorrhage, epidural hematoma, or diﬀuse axonal injury
Due to the clinical course of patients with these isolated traumatic intracranial hemorrhage
subtypes, these patients are unlikely to beneﬁt from administration of TXA.
Bleeding/clotting disorders
Patients will be excluded if they are known to have a bleeding or clotting disorder including
hemophilia, prior episodes of DVT/PE or are on anticoagulants (e.g. warfarin).
Known seizure disorders
Patients will be excluded if they are known to have a seizure disorder and are currently
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on medications for a seizure disorder. A history of febrile seizures is not considered a
seizure disorder. Patients who have had a prior seizure but are not currently on long-term
anti-seizure medication are eligible.
Severe renal impairment
Patients with impaired renal function may experience an increased elimination half-life
for TXA. Thus patients with known severe renal impairment (creatinine clearance less
than 29 mL/min/1.73m2) will be excluded. Similarly, if severe renal impairment is noted
on baseline or subsequent laboratory measurements then drug discontinuation rules will
be initiated. Patients with hepatic impairment will not be excluded. TXA is excreted
unchanged and thus dose adjustment due to hepatic impairment is not recommended.
Additionally, any elevations of hepatic enzymes or coagulation proﬁle are more likely to
be secondary to the patients traumatic injury and coagulopathy rather than due to the
use of TXA.
Repeat enrollment of subjects
Although we anticipate subjects are unlikely to present with multiple episodes of severe
trauma, a subject is only eligible to be enrolled into the study once.
Already received TXA for current injury
If the patient already received TXA for the current injury (pre- or in-hospital) they are
not eligible for the study.
Known venous or arterial thrombosis
We will exclude patients with known venous or arterial thrombosis.
2
Rationale and Background
2.1
Traumatic coagulopathy and hyperﬁbrinolysis increases mor-
bidity and mortality after pediatric trauma
Trauma is the leading cause of morbidity and mortality in children in the United States.8
Deaths in children with trauma are primarily from direct injury to critical organs (brain,
heart, lungs) or hemorrhage into the thoracic and/or abdominal cavities. In the initial
24 hours after injury, hemorrhage is the leading cause of death.9 The degree of hemor-
rhage is inﬂuenced by both the extent of injury to the structures and the occurrence of
trauma-induced coagulopathy. Traumatic coagulopathy is common after severe injury,
particularly in patients with brain injuries, acidosis, and/or shock and independently
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increases morbidity and mortality.10–13 Nearly 30% of injured children admitted to the
hospital have abnormalities of routine clotting parameters (INR and PTT) and 6% have
markedly abnormal values.14
Hyperﬁbrinolysis, or the premature and excessive breakdown of blood clots, is a major
component of traumatic coagulopathy.15 As measured by thromboelastography (TEG)
testing, hyperﬁbrinolysis has been shown to be present in 24% of severely injured children
and increases the risk for death six-fold compared to children without hyperﬁbrinolysis.16
Hyperﬁbrinolysis is also associated with the need for life-saving interventions and the
need for blood product transfusions in severely injured children.17
2.2
Targeting ﬁbrinolysis may attenuate post-traumatic hemor-
rhage and decrease blood product transfusion requirements
Tranexamic acid (TXA) is an antiﬁbrinolytic lysine analogue that blocks the conversion
of plasminogen to plasmin. Plasmin is central to ﬁbrinolysis as it is the enzyme catalyzing
the dissolution of ﬁbrin clots. Thus, the administration of TXA prevents the formation of
plasmin thereby preventing ﬁbrin clot breakdown. Premature and excessive ﬁbrinolysis
is a primary component of traumatic coagulopathy and hemorrhage progression due to
elevated levels of tissue plasminogen activator (t-PA) commonly seen after traumatic
injuries, particularly TBI.18
Recent evidence in injured adults indicates that treatment with TXA decreases
mortality and blood-transfusion requirements following traumatic hemorrhage.19 The
Clinical Randomization of an Antiﬁbrinolytic in Signiﬁcant Haemorrhage-2 (CRASH-2)
trial randomized 20,211 adult trauma patients at risk for signiﬁcant hemorrhage to TXA
or placebo. If administered within 3 hours of injury, TXA reduced the risk of death from
bleeding by approximately one-third.20 Furthermore, TXA had an excellent safety proﬁle
and was found to be cost-eﬀective for use in these injured adult trauma patients.21 Based
on the results of the CRASH-2 trial, administration of TXA is considered standard-of-care
for severely-injured adults with hemorrhagic trauma and is included on the World Health
Organizations list of essential drugs.
Because TXA attenuates hemorrhage, it has the potential to improve clinically-
important outcomes after TBI. Two phase-II clinical trials in adults with TBIs demon-
strated a trend towards decreased intracranial hemorrhage progression with TXA use,
and decreased mortality and improved functional outcomes.22–24 The promising results of
these trials led to the start of two large-scale, phase III trials, evaluating the use of TXA
for adults with TBI.25, 26
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2.3
TXA has not been appropriately studied in children with
hemorrhagic injuries
Unfortunately, applying results of adult studies to children is inappropriate for several
reasons. Children diﬀer from adults with regards to anatomy, physiology, psychological
development, mechanisms of injury and outcomes. Data regarding TXA use in children
is mostly limited to those undergoing certain elective surgeries, speciﬁcally cardiac
surgery,27–29 with some small studies in children undergoing spinal and craniofacial
surgeries.30 These data suggest that perioperative administration of TXA decreases
blood transfusion requirements in children.27–30 Furthermore, these studies suggest an
excellent safety proﬁle for TXA use in children. The type of traumatic insult and degree
of inﬂammation and its impact on coagulation in these elective surgeries, however, is
likely diﬀerent than that following hemorrhage from multisystem trauma.
One retrospective study evaluated the impact of TXA administration in children
injured in Afghanistan. After controlling for injury severity, TXA substantially reduced
mortality (odds ratio = 0.28, 95% CI 0.09, 0.89).31 Unfortunately, only 66 (9%) of the
766 children in the database actually received TXA. Of note, there were no diﬀerences in
venothromboembolic events between those who did and did not receive TXA.
Based on the TXA studies in injured adults, the evidence of safety and eﬀectiveness
in children undergoing non-traumatic surgical procedures and the limited study of TXA
in injured children, there is great potential that TXA may safely reduce blood transfusion
requirements (and morbidities) in injured children. Not surprisingly, determining if TXA
is beneﬁcial and safe in injured children is a top priority for numerous stakeholders.32–34
3
Study Design and Data Collection
3.1
Study Design Overview
This pilot study is a double-blind, randomized controlled trial of children younger than 18
years old with hemorrhagic injuries to the torso or brain. Children will be randomized to
one of three arms: 1) TXA dose A (15 mg/kg bolus dose over 20 minutes, followed by 2
mg/kg/hr infusion over 8 hours), 2) TXA dose B (30 mg/kg bolus dose over 20 minutes,
followed by 4 mg/kg/hr infusion over 8 hours), and 3) normal saline placebo. The pilot
study will be conducted at 4 sites. This pilot study will be conducted in preparation for
a subsequent phase II/III seamless clinical trial of TXA administration for children with
hemorrhagic torso or brain injuries.
We plan to enroll 40 subjects (approximately 1.25 subjects per month at each of the 4
participating sites). The participating sites evaluate up to 10 subjects with signiﬁcant
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torso and cranial trauma monthly at their sites, therefore enrolling 1-2 per month at each
site should be feasible.
3.2
Participant Screening and Consent
Subjects will be identiﬁed and recruited in the EDs of all participating centers. Potentially
eligible subjects will be screened by the clinical research coordinators. Subjects believed
to be eligible will be discussed with the treating physicians and the study site investigative
team (clinician determined by each site and may include Site PI or Co-Investigators) to
conﬁrm eligibility. See section 7.2 and 7.3 for details of the consent process.
3.2.1
Missed Eligible Subjects
To assure that trauma patients recruited into this study are representative of the overall
trauma population a review of the trauma admission log/trauma database may be
conducted routinely during the screening and enrollment period of the trial. If a potential
study participant met eligibility criteria but was not approached, the research coordinator
will retrospectively complete a form with some basic demographic and clinical information
on these patients. This will help assess potential enrollment bias. The Site PI will then
discuss these cases with the nursing staﬀ, as well as both the attending trauma and
emergency physicians who failed to identify the patient as eligible for the study, as an
opportunity to improve future enrollment.
3.3
Baseline Data Collection
Baseline data recorded for all children will include age, sex, race and ethnicity, and any
other chronic medical conditions. At presentation to the ED we will also record vital
signs and physical examination ﬁndings. We will also collect baseline laboratory values
that are routinely collected as standard of care. To obtain information on ﬁbrinolysis,
we will also perform viscoelastic coagulation testing using thromboelastography (TEG).
TEG testing is the only research-related lab testing per study procedures.
Demographics and injury characteristics will be collected (e.g., mechanism of injury,
subject demographics, clinical information, and outcome).
Laboratory Data (collected if completed as standard of care procedures)
Examples of data elements:
• Creatinine
• CBC
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• INR/PT
Baseline Clinical Information
Examples of data elements:
• GCS score (or Pediatric GCS score for those younger than 2 years-old)
• Pupillary assessment
• Vital signs
• Presence of and types of traumatic brain injuries, abdominal injuries, thoracic
injuries, pelvic injuries, and orthopedic injuries
3.3.1
Biomarker testing
We will collect blood samples for TEG and other biomarker tests prior to the start of study
drug infusion (baseline) and throughout the infusion. The results of the biomarker testing
will be used for research purposes only and not be available to clinicians. The amount of
blood drawn at each blood draw will be no more than 5-10 mls, or approximately one
to two teaspoons of blood per blood draw. This is well below the maximum allowable
volume (ml) of blood drawn for research purposes in children (5% of total blood volume).
Thromboelastography (TEG) testing Fibrinolysis is evaluated based on the percentage
of clot lysis at 30 minutes post-maximum clot strength (LY-30) (Figure 2). The TEG
testing will also provide information on coagulation factor function (clot time [r-value] and
rate [k-time and alpha-angle]), and platelet function (maximum clot strength [maximum
amplitude]). The TEG testing will be completed as soon as possible after enrollment into
the study by the trained site-speciﬁc staﬀ. All sites have veriﬁed TEG testing availability
and processing time.
Although no studies have demonstrated an association between TEG directed man-
agement in injured patients and improved patient outcomes, TEG testing is emerging as
an eﬃcient method for the rapid diagnosis of post-traumatic coagulopathy. It is widely
used in the operating room to direct transfusion protocols and many authors feel that it
may have a similar role in the trauma setting.35–37 Hyperﬁbrinolysis deﬁned as a LY30
of 3% is an independent predictor of mortality (odds ratio 6.2, 95% CI 2.47 to 16.27)
in severely injured pediatric trauma patients.16 This increase in mortality with LY30
threshold of 3% is consistent with similar studies of adult trauma patients.38, 39 This
same pediatric trauma study also found hyperﬁbrinolysis occurred more frequently in
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Consent
Blood draw 1 for TEG and other 
biomarker testing 
Completion of infusion
Blood draw 2 for TEG and other 
biomarker testing  
Blood draw 1 for 
TXA level
24 h from start of drug
Randomization/ Start of study drug
End of bolus
TXA level 
(convenience)
Blood draw 2 for 
TXA level
TXA level 
(convenience)
TXA level 
(convenience)
Figure 2: Flow diagram of blood draws for biomarker testing and TXA levels
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children than similarly injured adults (24% vs. 9%).16 Other studies have suggested
diﬀerent thresholds for deﬁning hyperﬁbrinolysis40 or other diagnostic measures such as
rotational thromboelastography41 or plasmin-antiplasmin complex levels.42, 43 However
these diagnostic measures are limited by their availability in the US44 and their lack of
real time results.43, 45 Given the ability for TEG testing to provide clinicians quickly
with data on ﬁbrinolysis after trauma, TEG has been suggested as a means to directing
antiﬁbrinolytic therapy.12, 39, 46
The objective of obtaining TEG testing (see TEG parameters in Figure 3) for the
pilot study is to demonstrate the feasibility of collecting TEG as part of study procedures.
Potential issues such as timing of blood collection and blood processing have not been
evaluated in a multicenter pediatric trauma trial. We will not analyze the association
with TEG results and outcomes in the pilot study due to the small number of subjects
enrolled, however we anticipate this analysis for the subsequent phase II/III trial.
Figure 3: TEG parameters
Other biomarkers In addition to TEG, we will also measure other biomarkers that
directly or indirectly measure ﬁbrinolysis. Examples of these plasma biomarkers include:
plasmin and d-dimer levels.
3.4
Data Collection During Hospitalization
Data collection during the ED stay and hospitalization is summarized in the Schedule
of Evaluations (Figure 4 on page 23). After the initiation of treatment and recording of
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baseline clinical and biochemical data, protocol procedures and ongoing data collection
will continue for 7 days or until hospital discharge (whichever comes ﬁrst).
3.4.1
TXA levels
We will collect blood samples at the end of the study drug bolus and again at the end
of the study drug infusion to measure TXA levels (Figure 2 on page 20). In addition to
these two blood samples, we will collect blood samples from routine blood draws during
the ﬁrst 24 hours after the start of study drug administration to measure serum TXA
concentrations. In addition to these two blood samples, we will also collect blood samples
during routine blood draws during the ﬁrst 24 hours after ED arrival. The results from
the TXA level measurements will be used for research purposes only and not be available
to clinicians.
3.4.2
GCS score assessment and pupillary examination
GCS score assessment and pupillary exam will be collected at baseline.
No repeat
physical examination testing will be mandated during the study. We will collect GCS
score assessment and pupillary examination results at 24 hours and at Day 7 or hospital
discharge (whichever comes ﬁrst) if completed as part of standard of care.
3.4.3
Blood product transfusion volume
Blood product transfusion volume will be measured at 24 hours, 48 hours, and 7 days or
hospital discharge (whichever comes ﬁrst) after randomization. This will include volume
of PRBCs, platelets, plasma, and cryoprecipitate.
3.4.4
Hospital discharge information
Information will be collected after hospital discharge. Examples of data elements collected
are:
• Hospital discharge date and time
• Destination upon discharge from hospital
• Abbreviated Injury Severity
• Mortality
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Figure 4: Schedule of Evaluations
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3.5
Follow Up Data Collection
3.5.1
Pediatric Quality of Life (PedsQL), Pediatric GOS-E, and digit span
evaluations
We will evaluate PedQL, Pediatric GOS-E, and the digit span recall test at Day 7, 1
month, 3 months, and 6 months post randomization. Subjects will be contacted via
telephone by central assessor for these assessments. Below are the allowed windows for
follow-up calls:
• 7 days = +7 day window
• 1 month = +14 day window
• 3 months = +4 week window
• 6 months = +4 week window
3.6
General Management Principles
To best discern the eﬃcacy of TXA in the subsequent trial, it will be important to limit
the variability of management of injured children. Heterogeneity of care such as diﬀering
transfusion practices or use of intracranial pressure monitoring devices may confound any
potential eﬃcacy or harm of TXA. However eﬀorts to standardize general management
principles must be balanced with the overall lack of deﬁnitive evidence on pediatric
transfusion practices and TBI management. Each site will have an emergency physician,
a trauma surgeon, a pediatric neurosurgeon, and a blood transfusion medicine physician
included as co-investigators to assist in overseeing general management principles for this
trial.
4
Study Procedures
4.1
Randomization (Enrollment)
Due to the narrow time window of study intervention, randomization must not delay treat-
ment. To complete the randomization quickly, the study intervention will be preassigned
using a central randomization process. Prior to enrollment at each site, a study drug box
containing a vial of blinded study drug with a numeric identiﬁcation code corresponding
to the treatment assignment will be designated as the “Use Next Box.”
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“Use Next Box”
Because we will be evaluating TXA for diﬀerent injury patterns (hemorrhagic torso
injury, hemorrhagic brain injury, and hemorrhagic torso and brain injuries), randomization
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will be stratiﬁed by injury type. Eligible subjects will be randomized into one of the three
arms in a 1:1:1 ratio (TXA dose A, TXA dose B, or placebo). We will perform block
randomization across types of injuries (i.e., torso or, brain or both torso and brain). To
ensure suﬃcient number of injury types, we will limit the enrollment of subjects meeting
the inclusion criteria for isolated brain injury (i.e., GCS less than or equal to 13 with
associated intracranial hemorrhage) to a total of 20 subjects (as it is anticipated these will
be the most common eligible subjects evaluated at the participating sites). Randomization
will occur when drug infusion starts.
4.2
Study Drug Administration
4.2.1
Rationale for Study Doses
Enrolled subjects will be randomized to one of three study arms: TXA dose A, TXA dose
B, or placebo. A systematic review demonstrated substantial variability in TXA dosing
for pediatric surgical subjects, ranging from initial loading doses from 2 to 100 mg/kg IV,
and a continuous infusion ranging from 3 to 10 mg/kg/hr.30 Doses selected for this study
and rationale are as follows:
• TXA dose A arm: Subjects will receive a 15 mg/kg bolus of TXA over 20 minutes
followed by a 2mg/kg/hr infusion over 8 hours. The maximum bolus dose is 1000 mg,
the maximum rate of infusion is 50 mg/min, and the maximum total maintenance
dose is 1000 mg. This represents 31mg/kg total dose of TXA. This dosage is based
on the dose studied in the CRASH-2 trial and has been recommended by a prior
evidence statement (see Royal College of Paediatrics).? This dose is estimated to
inhibit approximately 80% of ﬁbrinolysis based on prior studies (Figure 5 on the
facing page).47
• TXA dose B arm: Subjects will receive a 30 mg/kg bolus of TXA over 20 minutes
followed by a 4 mg/kg/hr infusion over 8 hours. The maximum bolus dose is
2000 mg, the maximum rate of infusion is 100 mg/min, and the maximum total
maintenance dose is 2000 mg. This represents 62 mg/kg total dose of TXA. This
dosage represents approximately the 75th percentile dosage for children receiving
TXA for non-traumatic surgical procedures in the PHIS database48 and is estimated
to inhibit 100% of ﬁbrinolysis.47 This dose is within the range recommended by the
WHO49 and has not demonstrated an increase in adverse events.30
• Placebo arm: Subjects in the placebo group will receive a bolus dose of normal
saline over 20 minutes followed by a normal saline infusion over 8 hours (in the
same weight-based volume as the other study arms).
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Figure 5: Plasma concentrations of TXA by dosing (Adapted from Koster et al.47).
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In Figure 5, colored bars represent two diﬀerent drug concentrations of IV bolus and
infusion dosing from two prior studies (Bojko et al50 and Grassin-Delyle et al51) and the
subsequent measured TXA plasma concentration. A TXA plasma concentration of 20
mcg/ml inhibits approximately 80% of ﬁbrinolysis and a concentration of 100 mcg/ml
inhibits 100% of ﬁbrinolysis.52
The UC Davis Good Manufacturing Practice Laboratory (Sacramento, CA) will
prepare, package and store the investigational drug products (2 TXA arms) and the
placebo arm at 2-8 ◦C. Both TXA infusions and the placebo infusion will be identical
in color, volume, and packaging. The study drugs will be packaged in 100 ml glass
infusion vials and will be clear and colorless. The concentration of TXA dose A will be
20 mg/ml of TXA in normal saline, TXA dose B will be 40 mg/ml of TXA in normal
saline, and placebo will be 100 ml of normal saline. Each drug vial will have: 1) a numeric
identiﬁcation code that corresponds to the treatment assignment, 2) a label reminding
clinical staﬀand study team members that weight-based dosing will be used, 3) a colored
sticker identifying study vial by stratiﬁcation, and 4) a hanger loop that can be peeled oﬀ
to create a hanger.
4.2.2
Manufacturing and Distribution of the Study Drug
Example of study label
The study kits will
be shipped to the
clinical sites from
the UC Davis GMP
facility at 2-8
◦C.
Shipping will be con-
ducted under con-
trolled conditions un-
der a chain of cus-
tody documentation
and a data log in-
cluded in shipment.
The product will be
stored by the IDS
Pharmacies at the
sites at 2-8 ◦C until dispensed. The IDS Pharmacies will store at least 1 study vial
for each study arm. The number of vials stored at each IDS Pharmacy may be modiﬁed
depending on the rate of enrollment for each site.
After enrollment, the study vial numeric identiﬁcation code will be entered into an
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online data management system by the study team. The study team will obtain a backup
study vial from the IDS Pharmacy, corresponding to the recently used study vial (e.g.,
torso study vial will replace torso study vial). The backup study vial will then be placed
in the corresponding Use Next Box that will be stored in a secure automated medication
dispensing system in the ED. There will be Use Next Boxes for each study arm in the ED.
Each Use Next Box will contain a corresponding study vial and a weight-based dosing
chart described below.
All individuals providing clinical care at the study sites (physicians, nurses, laboratory
technicians, respiratory therapists, pharmacists, etc.) and the study team (research
coordinators, research assistants, and site investigators) will be blinded to allocation and
dosing, as will the subjects.
4.2.3
Study Drug Administration
The study box will be stored in a secure automated medication dispensing system in
the ED at temperatures 2-8 ◦C. When a subject is ready to be enrolled into the study
(Figure 8 on page 33), a member of the clinical staﬀwill remove the “Use Next Box”
from the secure automated medication dispensing machine in the ED and follow the
weight-based dosing chart provided in the box. An infusion pump will be programmed
with the determined rate and volume of the bolus and maintenance dose. All doses of
study drug will be administered intravenously. An initial bolus dose will be given to the
subject over 20 minutes, immediately followed by the maintenance infusion over 8 hours.
Rates are provided on the dosing chart. Each 100 ml vial of study drug will have suﬃcient
volume of study drug for both the bolus and infusion doses. After enrollment, the study
team will load the study site’s back-up vial into the “Use Next Box”. There will be three
“Use Next Boxes” one for torso injuries, one for brain injuries and one for both torso and
brain injuries, each with a corresponding study vial.
For children weighing less than 35 kg, a syringe pump with a volume of 60 ml will
typically be used. If a syringe pump is used, the total volume for both the bolus and
maintenance infusion will be withdrawn (plus an additional 2 ml to account for priming
of the syringe pump tubing) from the 100 ml study vial and loaded into the syringe pump.
The infusion line will be primed with study drug (typically 2 ml) prior to infusion. At
the end of the maintenance infusion, the syringe pump tubing will be disconnected and
discarded. The infusion line will not be ﬂushed.
For children weighing 35 kg or more, it is recommended that the 100 ml study vial
will be directly spiked with a standard vented IV administration set. The vial will be
inverted and hung from the attached plastic loop. The infusion line will be primed with
study drug (typically 10-14 ml). At the end of the maintenance infusion, there may be
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remaining study drug within the infusion line. A suﬃcient amount of sterile 0.9% sodium
chloride may be used to ensure that all remaining study drug is infused from the line and
administered to the subject.
The study arms will be blinded. Therefore, the same weight-based volume will be
infused for each arm. The volume for the infusion will be determined by the estimated
or calculated weight of the child. The weight-based dosing for all arms are described in
Figure 6 on the facing page.
The weight-based dosing in Figure 6 on the next page corresponds to the total doses
of TXA dose A and TXA dose B displayed in Figure 7 on page 32.
For children with moderate renal impairment(estimated glomerular ﬁltration rates
30-59 mL/min/1.732 [as calculated by the bedside Schwartz method]) we will reduce the
dose by 50%. This will be accomplished by reducing the rate of study drug administration
by 50%. For example, if the child weighs more than 60 kg, the maintenance infusion rate
should be 6.25 ml/hr over 8 hours. If moderate renal impairment is identiﬁed, the rate
will be reduced to 3.125 ml/hr over 8 hours. This rate adjustment will occur as soon
as moderate renal impairment is identiﬁed. If severe renal impairment is identiﬁed, the
study drug will be discontinued.
4.2.4
Discontinuation of Study Drug
The study drug will be discontinued if any of the following occur:
• Suspected anaphylactic reaction
• Severe renal impairment (creatinine clearance less than 29 mL/min/1.73m2) is
identiﬁed on baseline or subsequent laboratory measurements
• Withdrawal of consent by the subject’s legal guardian or legally authorized repre-
sentative
• Discovery of new information which makes the subject ineligible to continue partici-
pation in the study (e.g.,exclusion criteria such as pregnancy, prisoner, history of
seizures or clotting disorders)
4.3
Blinding and Unblinding
Both subjects and study team members are blinded to the interventional arm. Blinding
is provided by the use of identical study drugs, packaging, volume, and rate of infusion.
Unblinding is not allowed. Clinicians should assume that the subject has received
TXA and treat accordingly.
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Estimated 
weight in kg 
(calculated 
weight) 
BOLUS 
volume 
(TXA Arm 
A, B, or 
placebo) 
(total ml) 
BOLUS rate 
(ml/hr) over 
20 min 
MAINTE-
NANCE 
volume (TXA 
Arm A, B, or 
placebo) 
(total ml) 
 
MAINTE-
NANCE 
rate 
(ml/hr) 
over 8 
hours 
Length 
based 
color on 
Broselow 
tape 
3-4.9 
3 
9 
3 
0.375 
Grey 
5-7.4 
5 
15 
5 
0.625 
Pink 
7.5-9.9 
7 
21 
7 
0.875 
Red 
10-12.4 
9 
27 
9 
1.125 
Purple 
12.5-14.9 
11 
33 
11 
1.375 
Yellow 
15-19.9 
14 
42 
14 
1.75 
White 
20-24.9 
18 
54 
18 
2.25 
Blue 
25-29.9 
22 
66 
22 
2.75 
Orange 
30-34.9 
26 
78 
26 
3.25 
Green 
35-39.9 
30 
90 
30 
3.75 
 
40-49.9 
36 
108 
36 
4.5 
 
50-59.9 
44 
       132   
44 
5.5 
 
>60 
50 
150 
50 
6.25 
 
 
Figure 6: Weight-Based Dosing for All Arms
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Figure 7: Weight-Based Dosing of TXA Dose A and TXA Dose B
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Figure 8: Study Flow Chart
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5
Data Analysis
5.1
Outcomes
As this study is a pilot trial to collect preliminary data on safety and eﬃcacy and to assess
feasibility of study procedures, the study is not powered for a particular endpoint. We will
collect the following outcomes: total blood products (ml/kg) transfused over the initial
48 hours of care (children with torso injury), and intracranial hemorrhage progression in
ﬁrst 24 hours (children with TBIs). We will also measure PedsQLTM (Pediatric Quality
of Life Inventory), Peds GOS-E, and digit span recall at 1 week, 1 month, 3 months, and
6 months post-randomization (all subjects) Figure 9.
Randomized 
Patient
Isolated 
Torso
Torso  + 
TBI
Isolated 
TBI
Torso Analysis: Peds QL (primary), Peds GOS-
E, digit span test, biomarker tests, 48 hour 
transfusion requirements, adverse events
TBI Analysis: PedsQL (primary), Peds
GOS-E, digit span test, biomarker tests, ICH 
progression, adverse events
Figure 9: Outcome Determination
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5.1.1
Blood Transfusion
Blood product transfusion will be calculated as the total mL/kg from randomization to
48 hours after randomization. Blood products used in the calculation will include packed
red blood cells (PRBC), platelets, fresh frozen plasma (FFP), and cryoprecipitate.
Rationale: Management of children with signiﬁcant traumatic hemorrhage involves
both the cessation of active bleeding and administration of blood products to correct for
hemorrhage-induced anemia and coagulopathy. Most of the initial and ongoing hemorrhage
occurs in the ﬁrst 48 hours after injury.53 While patients with substantial blood loss
and/or trauma-induced coagulopathy can beneﬁt from blood product transfusion, it
is not without substantial risk. Transfusion of PRBCs after trauma is independently
associated with increased risk of death and adverse events.54, 55 Transfusion of blood
products is associated with the transmission of infectious diseases, immune sensitization,
post-operative infectious complications, transfusion related acute lung injury (TRALI),
renal dysfunction, multiple organ failure, increased intensive care unit and hospital length
of stay, and increased short- and long-term mortality.56, 57 Surgical data suggests that
with each unit of PRBC transfused, the risk for an adverse outcome is incrementally
increased. It is estimated that 0.5 to 3% of all transfusions result in some adverse event.57
Transfusion of blood products is also costly. Based on a study published in 2006, the
cost of transfusing a single unit of PRBCs is between 1,600 US dollars and 2,400.58 US
dollars. Blood transfusion costs are also steadily increasing and will continue to increase
over time as additional blood product safety and screening measures are implemented.59
Additionally, blood transfusion related adverse events account for increased costs, largely
the result of increased hospital length of stay.59
Prior to the start of the study, the collaborating trauma surgeons and collaborating
transfusion medicine physicians (1 from each site), as well as other collaborators including
EM and ICU physicians, will establish general guidelines for indications for blood product
transfusion.
5.1.2
Intracranial Hemorrhage Progression at 24 hours (plus or minus 6
hours)
We will measure intracranial hemorrhage progression at 24 hours in all subjects with
intracranial hemorrhage on the initial clinical CT scan (excluding those who received a
neurosurgical intervention). We will perform a second non-contrast head CT scan 24 (plus
or minus 6) hours after randomization, for research, to assess intracranial hemorrhage
progression (for those who have not received a second head CT scan in the speciﬁed
time frame in the course of clinical care). Additional brain-imaging studies may be
performed at the discretion of the treating physician as a part of routine care. A central
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radiologist, blinded to clinical data, will review cranial CT scans and calculate intracranial
hemorrhage progression using the ABC/2 volume estimation.60 Intracranial hemorrhage
will be assessed relative to the total brain volume (calculated by the XYZ/2 volume
estimation).61, 62
Rationale: Most intracranial hemorrhage progression occurs in the ﬁrst 24 hours of
injury.63, 64 Intracranial hemorrhage size is strongly associated with functional outcomes.65
Given that TXA attenuates hemorrhage, intracranial hemorrhage progression is an
important outcome measure for subjects with TBIs.65
5.1.3
PedsQL
We will assess neurocognitive functioning and other quality-of-life measures using the
Pediatric Quality of Life Inventory (PedsQL) at 1 week, 1 month, 3 months, and 6 months
for all enrolled children.
Rationale: The PedsQL measures health-related quality of life in healthy children and
adolescents as well as those with acute and chronic health conditions.66 The PedsQL
generic core scales are comprised of 23 questions that measure the core dimensions of
health as delineated by the World Health Organization. The four multidimensional scales
include: physical functioning (8 items), emotional functioning (5 items), social functioning
(5 items), and school functioning (5 items). These four scales produce three summary
scores: total scale score (23 items), physical health score (8 items), and psychosocial
health score (15 items). The PedsQL is practical (less than 4 minutes to complete),
developmentally appropriate, reliable (excellent correlation between child self-report and
parent proxy-report), valid (distinguishes between healthy children and children with acute
and chronic health conditions), and has been translated into multiple languages. There
are more than 850 publications reporting research that has used the PedsQL measure.
For TBI, PedsQL is reliable in diﬀerentiating between moderate and severe TBI.67 The
PedsQL has been recommended by the Common Data Elements (CDE) TBI Outcomes
Workgroup (in conjunction with NINDS) as a core quality-of-life measure post-TBI and
a primary measure of global outcome.68 The PedsQL is a continuous score that ranges
from 0-100. A clinically meaningful diﬀerence has previously been shown to be 4.5 points
on the PedsQL scale (minimum diﬀerence that subjects and their parents perceive to be
important).69 The PedsQL will be administered to subjects over the telephone.
5.1.4
Glasgow Outcome Score Extended (GOS-E) Peds
We will assess GOS-E Peds at 1 week, 1 month, 3 months, and 6 months for all enrolled
children.
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Rationale: The GOS-E Peds was developed as an age-appropriate, valid measurement
of outcome necessary to complete randomized clinical trials in infants and children less
than 17 years of age with TBI. The GOS-E Peds has been demonstrated discriminant
validity for mild, moderate, and severe TBI and is associated with changes in TBI sequelae
over time.66 The GOS-E has been recommended as a core measure global outcome in
TBI studies.68 For this proposal, the PedsQL and GOS-E Peds assessments will be
administered to all enrolled subjects over the telephone.
5.1.5
Digit Span Recall Test (working memory)
We will assess working memory using the digit span recall test at 1 week, 1 month, 3
months, and 6 months for all enrolled children 3 years and older.
Rationale: The digit span recall test evaluates working memory.70–72 Participants are
asked to repeat a series of numbers heard aloud, in the same order as spoken (forward
digit span), and then are asked to do the same backwards. The forward task measures the
ability to maintain information in line, whereas the backward task measures the ability to
mentally manipulate information.73 The examiner increases the numbers of digits by one
unit on each successive trial as long as the child repeats them correctly. The test ends
when the child makes a mistake in two sequences in the same span in a row.
5.1.6
Biomarkers
For each candidate biomarker, we will compute the within-person time 1 to time 2 change
score and then estimate between-group (high-dose vs. low-dose TXA) diﬀerences in mean
changes, along with 95% conﬁdence intervals.
5.1.7
Safety Outcomes
Safety outcomes will be assessed at Day 7 or at hospital discharge (whichever comes ﬁrst)
via review of the electronic medical record and include:
• Thromboembolic disease: any venous or arterial thrombosis on standard diagnostic
imaging post-randomization (including deep vein thrombosis, pulmonary embolism,
sinus thrombosis, myocardial infraction, ischemic stroke)
• Seizures occurring within the initial 24 hours of drug: clinical or electroencephalogram-
documented (seizures are a possible side eﬀect of TXA)
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5.2
Randomization and Stratiﬁcation
Subjects will be randomized into one of three arms (TXA dose A, TXA dose B, or
placebo). Subjects will undergo block randomization to ensure equal distribution of types
of injuries across the three arms Figure 10. To ensure suﬃcient number of injury types,
we will limit the enrollment of subjects meeting the inclusion criteria of GCS score less
than or equal to 13 with intracranial hemorrhage (Isolated TBI) to a total of 20 subjects
(as these are the most common subjects evaluated at the participating sites).
Figure 10: Block Randomization
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6
Data Management
6.1
Clinical Site Data Management
The Data Coordinating Center will create the electronic data capture (EDC) system
and worksheets that can be used by clinical site research coordinators and investigators.
Data will be entered via the Web into the EDC. Worksheets and study documents will be
maintained in locked ﬁling cabinets in locked oﬃces at each site.
6.2
Electronic Data Capture System
The Data Coordinating Center currently uses OpenClinica, REDCap, and XNAT as its
data capture systems; this may be changed at any time without requiring a protocol
amendment.
6.3
Study Monitoring
The investigators recognize the importance of ensuring data of excellent quality. Site
monitoring is critical to this process. Site monitoring has been a very eﬀective tool for
maintaining data quality in previous PECARN studies, and we will utilize this process
to ensure excellent quality data in the proposed study. Our site monitoring plan is
designed to identify problems with sites and methods for handling problems that arise.
Site monitors must be provided with full access to study materials and the medical records
for study subjects. If the medical records are in electronic form, the clinical investigator
or an authorized individual must provide any assistance necessary to facilitate the site
monitor’s review of data in the electronic medical record.
6.3.1
Site Monitoring Plan
A supplemental study-speciﬁc monitoring plan, separate from the protocol will be com-
pleted which outlines speciﬁc criteria for monitoring. This plan will include the number of
planned site visits, criteria for focused visits, or additional visits, a plan for chart review
and a follow up plan for non-compliant sites. The monitoring plan also describes the type
of monitoring that will take place (e.g. sample of all subjects within a site; key data or all
data), the schedule of visits, how they are reported and a time frame to resolve any issues
found. Remote site monitoring schedules will be determined by the Data Coordinating
Center in coordination with the study principal investigators.
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6.3.2
Clinical Site Monitoring
Site monitoring visits will be performed by a trained site monitor during the study
period to ensure regulatory compliance, patient safety, and to monitor the quality of data
collected. Essential document binders, regulatory documents and data collection forms
may be reviewed. Interim visits will take place depending on grant budget, site enrollment,
and compliance issues identiﬁed. The site monitor will provide each site with a written
report, and sites will be required to follow up on any deﬁciencies. It is anticipated that
the study monitoring visits for this protocol will consist of a site initiation visit (prior
to patient enrollment), interim visits, and a close out visit. The site initiation may take
place as group training made up of site investigators and research assistants.
6.3.3
Remote Monitoring
The Data Coordinating Center may supplement on-site monitoring with remote monitoring
activities. Remote monitoring involves detailed review of the data entered by the Clinical
Center and consultations with the Clinical Center investigator and/or research coordinator
to review safety and data quality. This may require uploading de-identiﬁed copies of
speciﬁc parts of the medical record, subject study ﬁle, regulatory documentation, or other
source documents to the Data Coordinating Center staﬀ, who review those materials
against the data recorded in the electronic data capture system. This helps assure protocol
compliance and accurate data collection. The Data Coordinating Center may conduct
more remote monitoring activities early in the trial to assure protocol compliance and
identify any training issues that may exist. Remote monitoring the documents will be
retained in accordance with federal requirements. Safety of subjects will be monitored
and ensured in accordance with the Data and Safety Monitoring Board (DSMB) plan.
6.3.4
Pharmacy Monitoring
The Clinical Center pharmacy must maintain adequate records of all dispensed study
drug. Each pharmacy will be monitored and may be requested to send copies of these
documents to the Data Coordinating Center. Since this study will use a central pharmacy,
that pharmacy must also maintain adequate records and will also be monitored.
6.4
Data Coordinating Center
6.4.1
Data Center Description
The Data Coordinating Center (DCC) in the Department of Pediatrics at the University
of Utah School of Medicine provides data coordination and management services for a
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variety of national research networks. Anchoring these services is a new state-of-the-
art, energy eﬃcient data center completed in 2013. The data center facility supports
more than 1400 users around the world and provides a secure, reliable, enterprise-wide
infrastructure for delivering critical DCC systems and services. The new data center
was built using high industry standards and energy eﬃcient cooling solutions. The data
center is cooled by Rittal’s LCP inline cooling technology, providing eﬃciency, redundancy
and modularity. Cooling is based upon a hot/cold aisle design that allows for even air
distribution with minimal hot spots. The data center electrical power system contains a
redundant Mitsubishi uninterruptible power system (UPS) with a diesel backup generator.
The data center is protected with a FM200 ﬁre suppression system, early warning smoke
detectors and a heat detection warning system to act as a secondary system to the smoke
detectors. Security guards are on-site conducting access control and rounds 24/7/365.
Entry into the data center is restricted by card access and layered security measures and
controls. The data center and external building access points are monitored with video
surveillance.
In 2011 the data center began a large scale VMware server virtualization deployment.
Currently, the data center has virtualized about 99% of its environment. The virtual
environment consists of more than 200 virtual servers. The data center’s virtualization
solution provides key advantages:
• high availability – in the event of hardware failure, virtual servers automatically go
back online in a seamless process.
• ﬂexible infrastructure – disk storage, memory and processor capacity can be increased
or reallocated at any time.
• rapid deployment – servers can be provisioned on-demand with minimal waiting on
hardware of software.
The data center also enhanced its storage resources by implementing a networked
storage system to support its virtualized environment. The data center currently manages
over 50 terabytes of data. The storage solution consists of Dell’s EqualLogic PS Series
Storage system for providing a virtualized storage area network (SAN). Some of the
beneﬁts that are realized through this technology are:
• storage architecture is no longer be a bottleneck for IT services;
• performance is better than with the previous architecture;
• tiered storage is now possible;
• provisioning and reclamation of SAN disk will be much easier; and most important,
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• the new architecture includes a redesign of the SAN fabric to include complete
redundancy.
Production servers running critical applications are clustered and conﬁgured for failover
events. Servers are backed up with encryption through a dedicated backup server that
connects across an internal 10 gigabit network to a tape drive. DCC storage area net-
working (SAN) applications, clusters, and switch-to-switch links are also on a 10 gigabit
network. Incremental backups occur hourly Monday through Friday from 6 am to 6 pm.
Incremental backups also are performed each night with full system backups occurring
every Friday. Tapes are stored in a ﬁreproof safe inside the data center facility, and full
backups are taken oﬀsite on a weekly basis to an oﬀ-site commercial storage facility.
In the event of catastrophic failure, such as a ﬁre in the server facility, daily backups
would probably survive because of the ﬁre suppression system and ﬁreproof safe, but there
would be obvious delay in re-establishing data center function because the servers will not
survive such a disaster. Total destruction of the data center facility could cause the loss
of up to one week’s data. In future investments, the data center is making co-location,
disaster recovery and business continuity solutions a top priority.
DCC information systems are available 24 hours a day, 7 days a week to all users
unless a scheduled maintenance interruption is required. If this occurs, we notify all users
of the relevant systems, and data entry can be deferred until after the interruption is over.
Critical systems availability has exceeded 99.9% for the past two years, and there has
been no unscheduled downtime in over ﬁve years.
6.4.2
Security and Conﬁdentiality
The data center coordinates the network infrastructure and security with the Health
Sciences Campus (HSC) information systems at the University of Utah. This provides us
with eﬀective ﬁrewall hardware, automatic network intrusion detection, and the expertise
of dedicated security experts working at the University. Network equipment includes four
high-speed switches. User authentication is centralized with two Windows 2012 domain
servers. Communication over public networks is encrypted with virtual point-to-point
sessions using transport layer security (TLS) or virtual private network (VPN) technolo-
gies, both of which provide at least 128 bit encryption. All of our Web-based systems use
the TLS protocol to transmit data securely over the Internet. Direct access to data cen-
ter machines is only available while physically located inside our oﬃces, or via a VPN client.
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All network traﬃc is monitored for intrusion attempts, security scans are regularly run
against our servers, and our IT staﬀis notiﬁed of intrusion alerts. Security is maintained
with Windows 2012 user/group domain-level security. Users are required to change their
passwords every 90 days, and workstations time out after 5 minutes of inactivity. All ﬁles
are protected at group and user levels; database security is handled in a similar manner
with group-level access to databases, tables, and views in Microsoft SQL Server. Finally,
all laptop computers in use in the DCC or in the Department of Pediatrics are whole-disk
encrypted.
The data center uses control center tools to continuously monitor systems and failure
alerts. Environmental and network systems are also monitored to ensure up time. Highly
trained system administrators on staﬀare available to respond in high risk emergency
events.
All personnel involved with the DCC have signed conﬁdentiality agreements concerning
data encountered in the course of their daily work. All personnel (including administrative
staﬀ) have received Human Subjects Protection and Health Information Portability and
Accountability Act (HIPAA) education. We require all users to sign speciﬁc agreements
concerning security, conﬁdentiality, and use of our information systems, before access is
provided.
6.5
Record Access
The medical record and study ﬁles (including informed consent, permission, and assent
documents) must be made available to authorized representatives of the Data Coordinating
Center, upon request, for source veriﬁcation of study documentation. In addition, medical
information and data generated by this study must be available for inspection upon
request by representatives (when applicable) of the Food and Drug Administration (FDA),
NIH, other Federal funders, and the Institutional Review Board (IRB) for each study site.
7
Protection of Human Subjects
7.1
Institutional Review Board (IRB) Approval
The Data Coordinating Center and each clinical center must obtain approval from their
respective IRB prior to participating in the study. A central IRB (cIRB) at the University
of Utah will be used for this clinical trial.
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The Data Coordinating Center will track IRB approval status at all participating
centers and will not permit subject enrollment without documentation of initial IRB
approval and maintenance of that approval throughout subsequent years of the project.
7.1.1
Reporting of IRB Actions
Protocol Amendments Changes in the protocol which have been approved by the Central
IRB will be submitted upon IRB approval to the FDA, as required under 21 CFR 312.30(b),
and NHLBI prior to implementation. Upon notice that the protocol amendment has been
received at the FDA and NHLBI, the protocol amendment will be distributed to sites.
Sites will be instructed that they must follow local policies in implementing the protocol
amendment including obtaining local IRB approval, if required.
7.2
Informed Consent
We will enroll eligible patients who are younger than 18 years of age. Because eligible
patients are severely injured and will frequently arrive to the emergency department
(ED) without their parents or guardians, we will have a multifaceted approach to consent
(Figure 11 on the next page). We will attempt to obtain written informed consent at
the time of patient eligibility if the parent or guardian is available and able to provide
informed consent. However, because the therapeutic window of TXA is narrow, and
the parent or guardian will frequently be unavailable or unable to provide consent (e.g.,
severely injured or emotionally incapacitated) at the time that the patient is determined to
be eligible, we will also use federal Exception from Informed Consent (EFIC) procedures
as described below.
Parental Permission (when present and reasonable time to obtain informed
consent)
After determining that a subject is eligible, and the parent or guardian is present in the
ED and able to provide informed consent, the site investigator or designee will approach
the parent or guardian to oﬀer participation for their child in the study (Figure 12 on
page 46). The parent or guardian will be informed about the objectives of the study, the
study procedures, and the potential risks and beneﬁts of participation. If the parent or
guardian refuses permission for their child to participate, then all clinical management will
be provided by the clinical staﬀin accordance with institutional practice and judgment.
We will seek written documentation of parental permission from the subject’s parent
or guardian as soon as possible. Under FDA Regulation 21 CFR 50.55(e)(1), where
clinical investigations are more than minimal risk but presenting the prospect of direct
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Figure 11: Informed Consent Procedures
beneﬁt to individual subjects (50.52) and permission is to be obtained from guardians,
permission of one guardian is suﬃcient.
Under FDA Regulation 21 CFR 50.55(c)(2), because the intervention holds out a
prospect of direct beneﬁt that is important to the health or well-being of the child and
is available only in the context of the clinical investigation, assent of the child is not a
necessary condition for enrollment in the study.
Subject Consent
Subjects who are eligible for this study must be younger than 18 years of age at the time
of enrollment. If a subject reaches the age of 18 years after enrollment but during the
study period, then informed consent of the patient becomes applicable. If this occurs,
18 year-old subjects who are alert and competent and capable of giving consent will be
asked, following an appropriate discussion of risks and beneﬁts, to give consent to the
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Figure 12: Parent/guardian present and reasonable time to obtain informed consent
study for further study procedures. We will obtain informed consent from these subjects
for continuation in the study. Continued participation will consist of a telephone follow
up call, considered to be minimal risk. Subject consent will be waived if the subject has
a severely reduced mental age, decreased level of consciousness, psychological problems,
or other legitimate reasons as judged by the Institutional Review Board.
7.3
Exception from Informed Consent (EFIC)
We will use EFIC procedures when the parent or guardian is not present or unable to
provide written informed consent. See Section 7.3 for justiﬁcation of EFIC procedures.
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EFIC when the parent/guardian is not present or is unable to provide written
informed consent
We will enroll patients using EFIC procedures if the parent or guardian is not present or
is unable to provide written informed consent (e.g., parent is also severely injured or is
emotionally incapacitated) at the time eligibility is determined (Figure 13 on the next
page).
If the parent or guardian is not present at the time eligibility is conﬁrmed or is unable
to provide written informed consent, a family member who is present will be provided
the opportunity to object to the enrollment. In this scenario, the family member(s) will
be provided a brief overview of the study and an explanation on why we are unable
to obtain written informed consent due to the absence of the parent/guardian and the
narrow therapeutic time window. If the family member present objects to the patient’s
enrollment into the study, the patient will not be enrolled under EFIC procedures. If
no objections are made to the patient’s enrollment into the study, the patient will be
enrolled using EFIC procedures.
EFIC when the parent/guardian is present but there is not suﬃcient time to
obtain informed consent
We will enroll patients using EFIC procedures if the parent or guardian is present and
there is not suﬃcient time, at the time eligibility is conﬁrmed, to obtain written informed
consent and complete randomization. The parent and the guardian, however, will be
provided the opportunity to decline enrollment (Figure 14 on page 49).
In this scenario, the parent or guardian will be provided a brief overview of the study
and an explanation on why we are unable to obtain written informed consent due to the
narrow therapeutic time window. If the parent or legal guardian objects to the patient’s
enrollment into the study, the patient will not be enrolled under EFIC procedures. If the
parent or guardian agrees to the patient’s enrollment into the study, the patient will be
enrolled using EFIC procedures.
Obtaining informed consent after the use of EFIC
The use of EFIC does not obviate the need for parent or guardian consent. If EFIC
procedures are used, once the patient has been randomized and administration of study
drug has been initiated, the investigative team will attempt to obtain written informed
consent from the parent or guardian.
The parent or guardian will be informed of the patient’s inclusion into the study and
informed of the beneﬁts and risks of the study. At that time, the parent or guardian
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Figure 13: Parent/guardian absent or unable to provide informed consent
will be given the option of allowing the patient to continue in the study, or to cease the
subjects participation. If the parent or guardian requests that participation be stopped
during study drug infusion, the study drug will be stopped immediately, although the
parent or guardian will be asked if the patient could continue to be followed and evaluated
through the 6-month time point. If the parent or guardian agrees to allow the patients
continued participation or desires stopping the study drug, but will allow follow-up, an
appropriate written informed consent form will be signed by the parent or guardian.
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Figure 14: Parent/guardian present but not suﬃcient time to obtain informed consent
Justiﬁcation for EFIC
This research meets the criteria for EFIC speciﬁed in FDA Regulation 21 CFR 50.24 for
the following reasons:
• The human subjects are in a life-threatening situation that necessitates urgent
intervention;
Enrolled children will have signiﬁcant hemorrhagic injuries that are life-threatening.
• Available treatments are unproven or unsatisfactory;
Currently, no therapy is available to stop hemorrhage beyond surgical cessation.
No intravenous medications are available to assist in the cessation of hemorrhage.
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Thus, TXA has the potential to be the ﬁrst therapeutic medication in children with
hemorrhagic injuries.
• Collection of valid scientiﬁc evidence is necessary to determine the safety and eﬃcacy
of the intervention;
Scientiﬁc evaluation through a randomized clinical trial is necessary to further
test the eﬃcacy and safety of the proposed intervention.
• Obtaining informed consent is not feasible because the subjects are not able to give
their informed consent as a result of their medical condition;
Parents are frequently absent because either their children arrive in ambulances
without them or the parents are victims of the traumatic events that involve the
patients.
• The intervention must be administered before consent can be obtained from the
subjects parent/ guardian;
Obtaining informed consent from the patients parent/guardian is not feasible
due to the narrow therapeutic window of TXA. The greatest beneﬁt of TXA for
adults with hemorrhagic trauma is within one hour from the time of injury, and the
total therapeutic window is only up to 3 hours after injury. After 3 hours, there is
suggestion of harm from TXA infusion based on a large adult randomized control
trial of injured adults (Figure 15 on page 52).20
We have previously shown that 45% of children with head trauma present to the
ED without their parent or guardians.74 More importantly, more severely injured
children are more likely to present without a parent or guardian. Sixty-six percent
of children with GCS scores of 3 to 13 presented without a parent or guardian while
in children with GCS scores ≤8, none had a parent or guardian present at the time
of ED presentation.74 Our second study on the topic demonstrated across multiple
centers that among children with GCS scores of 3 to 12 following injury, the parent
or guardians for one-half of the patients do not present to the ED within the initial
3 hours of their child’s care.75
From a safety perspective, in the CRASH-2 trial evaluating TXA in adults with
hemorrhagic trauma, hospitals that waived the requirement for informed consent
started treatment 1.2 hours earlier (95% CI 0.7-1.8) compared to hospitals where
written consent was required from relatives (Figure 16 on page 53).76 Because
the beneﬁt of TXA is better the earlier it is administered, it was estimated that
this 1.2 hour delay reduced the proportion of patients who would have beneﬁtted
from the drug by 14%. Moreover, from a feasibility perspective, if all the sites
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required written informed consent for enrollment, the study would have likely been a
negative trial. A separate trial of adults with TBI evaluating the use of progesterone,
estimated the requirement for informed consent delayed enrollment by 4 hours based
on hypothetical modeling.77
• There is no reasonable way to identify prospectively individuals likely to become
eligible for participation;
There is no reasonable way to prospectively identify potential patients because
our patient population consists of trauma patients.
• Participation in the research holds out the prospect of direct beneﬁt to the subjects;
Pursuant to 21 CFR 50.24(a)(3): i) the proposed subjects are in life-threatening
situations requiring intervention, ii) prior pediatric and adult clinical data have
demonstrated clinical beneﬁts of TXA use suggesting the potential for direct beneﬁt
to the proposed subjects, and iii) these data have demonstrated no increase in
adverse events with the use of TXA, suggesting a reasonable risk-beneﬁt tradeoﬀfor
this condition. Thus, the potential beneﬁt of improved hemostasis, decreased blood
product requirements, hemorrhage attenuation/mitigation, and improved functional
outcomes substantially outweigh the risks, under FDA EFIC guidance.
• The clinical investigation could not practicably be carried out without the waiver;
Enrolling only patients that have their parent or guardians present within the
treatment window to consent would not be feasible and also create signiﬁcant
enrollment bias, thereby limiting the scientiﬁc validity of such a study design.
7.4
Waiver of Informed Consent
Waiver of consent is requested for observational data collection for each subject eligible
for this study. The justiﬁcation for waiver of consent for the observational data collection
in this study is based on the following factors:
1. The scientiﬁc validity of the study is dependent on capturing all eligible subjects
during the period of study, as one of the major goals is to accurately describe the
characteristics of the entire eligible population.
2. This part of the study involves no intervention and collection of observational data
will not require any subject or parent contact.
3. The minimal risk of loss of privacy is mitigated by secure data management at the
DCC, and analysis datasets will be de-identiﬁed.
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Figure 15: Mortality by time to treatment
7.5
Potential Risks
A systematic review of children undergoing non-traumatic surgery suggests no increased
risk of complications following TXA treatment.30 However, injured children were not
included in that systematic review and the authors acknowledge that none of the trials
included were powered to assess safety.30 The CRASH-2 trial, a large trial of TXA in
injured adults, also suggested no increased complications in the TXA group.19 Thus, we
do not anticipate an increased risk of complications in injured children receiving TXA
compared to placebo. The study, however, will monitor for speciﬁc potential risks as
described below.
The most important theoretical side eﬀect of TXA is acute thrombosis, either arterial
or venous.78, 79 Acute thrombotic events are deﬁned as vascular thrombosis resulting in
any of the following: cardiac ischemia, cerebral thrombosis, bowel infarction, deep venous
thrombosis, or pulmonary embolism. Seizures have been reported in cardiac surgery
patients receiving very high doses of TXA (61 to 259 mg/kg) with most receiving greater
than 100 mg/kg.80–84 Although, the seizures were believed to be related to cerebral
ischemia associated with the cardiopulmonary bypass rather than TXA,80 others have
suggested the seizures may be secondary to TXA inhibition of gamma-aminobutyric acid
receptors in neurons.81 Furthermore, the reported doses of TXA are substantially higher
than planned in this study. In addition, seizures are a complication of severe trauma,
especially in patients with traumatic brain injuries and those with episodes of hypoxia.
Thus, we will evaluate for these potential complications but do not anticipate that seizure
events are secondary to the doses of TXA planned for use in this study. Lastly, cerebral
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Figure 16: Eﬀect of 1 hour delay in start of treatment with TXA on proportion of patients
who will beneﬁt and on risk of death
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infarction may occur in patients with spontaneous subarachnoid hemorrhages.78, 85 Thus,
we will speciﬁcally assess for cases of cerebral infarction.
In addition to the above, subjects presenting with gross hematuria or renal injury who
do not meet exclusion criteria may still be at risk for ureteral obstructions. Investigators
should consider this possibility when enrolling subjects and should closely monitor urine
output and evaluate for ureteral thrombosis/obstruction in subjects with renal/bladder
injuries.
Other side eﬀects of TXA that we will monitor include symptoms listed in the package
insert such as gastrointestinal disorders (nausea, vomiting, and diarrhea) and allergic
dermatitis. These may occur at rate of 1-10%.
In addition to TXA administration, there may be added discomfort to the participant
with the additional blood collection. However, research samples will be collected at the
same time as a standard of care samples whenever possible to minimize extra needle
pokes to the participant. This research study may also involve one head CT scan for
head injury patients. This scan is not standard of care and study participant would be
receiving it only because they are enrolled in this research study. These procedures will
expose the participant to radiation. The risk from this radiation exposure is considered
to be small and comparable to other every day risks. To give an example of how much
radiation the participant will receive, we will compare this radiation to the radiation
that the participant receives from natural sources. Everyone receives a small amount of
unavoidable radiation every day. Some of this radiation comes from space while some
comes from radiation that is naturally occurring in water, soil, rocks and minerals found
in plants and animals. The excess radiation that the participant will be exposed to in
this research study is equivalent to about 9 months of natural background radiation. This
amount does not include any radiation exposures that the participant may receive from
other types of tests. Radiation exposure has the potential to lead to cancer later in life.
The exact risk is not known, but the risk is believed to be 2-5 times higher in children
than in adults exposed to the same radiation dose.
The risks to subjects in this proposal are reasonable in relation to the potential
beneﬁts of participation. The study risks will be minimized by very careful monitoring of
neurological, hemodynamic, and renal function status of study participants.
7.6
Protections Against Potential Risks
Subjects enrolled in the study will be monitored carefully for the development of any
potential complications as described above. Subjects will be evaluated frequently by the
treating team and at 24 (plus or minus 6) hours by the site investigator. If thrombosis
or seizure is suspected, prompt treatment will be administered per the routine of the
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treating facility. All study centers are tertiary care facilities with substantial pediatric and
pediatric trauma expertise and are well prepared to evaluate and treat any complications
that might arise.
All subjects discontinued early from the study protocol will have a reason for the
early discontinuation recorded on the appropriate case report form, and the circumstances
leading to discontinuation will be brieﬂy described. All adverse events (as described)
leading to discontinuation of study interventions will be fully documented and followed
up as appropriate.
Subjects who are discontinued early from the study protocol are not considered to be
withdrawn from the study, and will be included in the intention-to-treat analyses.
7.7
Potential Beneﬁts
Future patients with signiﬁcant traumatic injuries will beneﬁt from the study if the results
determine that TXA decreases complications from bleeding including the need for blood
transfusions and improves the patients quality of life.
7.8
Withdrawal from Study
For participants who withdraw from the study, the date and reason for consent withdrawal
must be documented. Otherwise, all subjects are followed for 180 days or death, whichever
comes ﬁrst, regardless of whether or not a subject has completed the study intervention.
It is important for safety to follow all subjects. Therefore, research staﬀwill conﬁrm
participants/parents wishes if they express the desire to withdrawal.
8
Data and Safety Monitoring Plan
8.1
Data Safety Monitoring Board (DSMB)
The study will have a Data Safety Monitoring Board (DSMB) approved by the funding
agency. The DSMB will be composed of a minimum of 5 members. The membership will
include representation from experts in the ﬁelds of pediatric trauma care, biostatistics,
bioethics, emergency medicine, and pediatric neurosurgery. The DSMB will have a charter,
will approve the protocol prior to implementation, and will review interim analyses as
applicable.
The purpose of the DSMB is to advise the sponsors and principal investigator(s)
regarding the continuing safety of study subjects and the continuing validity and sci-
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entiﬁc merit of the study. The DSMB is responsible for monitoring accrual of study
subjects, adherence to the study protocol, assessments of data quality, performance of
individual Clinical Centers, review of serious adverse events and other subject safety issues.
The DCC will send reports relating to these topics to DSMB members prior to each
DSMB meeting. The DCC will staﬀthe DSMB meetings and produce minutes of open
sessions. Minutes of closed or executive sessions of the DSMB will be produced and
retained by the DSMB Chairperson. These closed minutes will not be available outside
the DSMB prior to the end of the study. The DSMB Chairperson will prepare a summary
of each DSMB meeting that conveys the public conclusions of the DSMB, with respect to
protocol alterations and recommendations concerning continuation of the study. When
applicable, this will be sent directly to the study sponsor for approval before it is provided
to the DCC and sites. When the summary is provided to the DCC, the DCC will send the
summary to all Clinical Center investigators for submission to their respective Institutional
Review Boards/Research Ethics Board(s).
8.2
Frequency of Interim Analysis
The DSMB will be expected to meet every six months, including an initial meeting
prior to the start of subject enrollment and then after enrollment of the 10th subject
(anticipated 2-3 months after onset of subject enrollment). The DSMB, however, will
have the discretion to alter meeting timing and frequency.
8.3
Conﬂict of Interest
As described in the DSMB charter, DSMB members should be independent of all entities
sponsoring, organizing, conducting, or regulating the TIC-TOC study. Speciﬁcally, DSMB
members should not have any signiﬁcant ﬁnancial interest in the studys conduct or outcome,
nor be involved in the design of this study. Additionally, members must disclose any actual
or potential conﬂicts of interest involving pharmaceutical or biotechnology companies and
contract research organizations. This includes any ﬁnancial arrangement, consultancy
agreement (direct or via third party), research support, or any other relationship that
could be construed as introducing potential bias to their role as a DSMB member.
The DSMB and NHLBI Program Oﬃcer will be responsible for determining whether
any consultancies or ﬁnancial interests of a member may be viewed as potentially materially
impacting their objectivity. This decision is to be based on the reasonable belief that
objectivity is in doubt. Each DSMB member is responsible for informing the NHLBI
Program Oﬃcer and DSMB Chairperson if any relevant changes in ﬁnancial interest or
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other developments aﬀecting potential or perceived conﬂict of interest develop during the
duration of DSMB membership.
8.4
Adverse Event Reporting
Assuring patient safety is an essential component of this protocol. Each participating
site investigator will have primary responsibility for the safety of the individual subjects
under his or her care. All adverse events occurring after study randomization through
Day 7 or hospital discharge (whichever comes ﬁrst) will be recorded and entered into
the electronic data entry system provided by the DCC. In accordance with local IRB
requirements, the site investigator may be required to report such events to the IRB in
addition to notifying the DCC.
8.4.1
Deﬁnitions, Relatedness, Severity and Expectedness
Deﬁnition:
An adverse event (AE) is any untoward medical occurrence experienced by
a subject. An event constitutes a disease, a set of related signs or symptoms, or a single
sign or symptom. The site investigators will evaluate for adverse events throughout the
study period. Adverse events not previously documented in the study will be recorded
on the adverse event record form. The nature of each experience, date and time (where
appropriate) of onset, outcome, course, and relationship to treatment should be established.
Relatedness:
The suspected relationship between study interventions and any adverse
event will be determined by the site investigator using the following criteria. Relatedness
may not be assessed by a research coordinator, and must be assessed by an investigator.
Not Related: The event is clearly related to other factors, such as the subject’s clinical
state, therapeutic interventions, or concomitant drugs administered to the subject.
Possibly Related: The event follows compatible temporal sequence from the time of
beginning the assigned study intervention, but could have been produced by other
factors such as the subject’s clinical state, therapeutic interventions, or concomitant
drugs administered to the subject.
Probably Related: The event follows a reasonable temporal sequence from the time
of beginning the assigned study intervention, and cannot be reasonably explained
by other factors such as the subject’s clinical state, therapeutic interventions, or
concomitant drugs administered to the subject.
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Some toxicities will be diﬃcult to distinguish from abdominal symptoms related to acute
gastroenteritis (such as bloating, abdominal pain, diarrhea, fever and diaper rash), and
only at the time of analysis will we be able to determine whether these signs and symptoms
are diﬀerent between the groups.
Seriousness:
The severity of clinical adverse events and laboratory abnormalities will
be recorded by the site investigator and categorized. A serious adverse event (SAE) is an
adverse event that:
• results in death; or
• is life-threatening (the subject was, in the view of the site investigator, in immediate
danger of death from the event as it occurred); or
• requires inpatient hospitalization or prolongs an existing hospitalization; or
• results in persistent or signiﬁcant disability or incapacity; or
• results in congenital anomaly/birth defect; or
• any other event that, based upon appropriate medical judgment, may jeopardize
the subject’s health and may require medical or surgical intervention to prevent one
of the other outcomes listed in this deﬁnition.
Expectedness of the Event:
All adverse events, including serious adverse events, will
be evaluated as to whether their occurrence was expected or unexpected. An adverse
event is considered expected if it is known to be associated with TXA, other underlying
medical conditions of the subject, is known to occur with trauma, is directly related to
study outcome, or is otherwise mentioned in the protocol, informed consent, or other
study documents. An adverse event is unexpected when it is not expected as above or
occurs in a diﬀering severity or frequency than is described above.
Expected complications of traumatic injuries include all of the following: seizures,
venous thromboses (including pulmonary emboli), acute kidney injuries (including kidney
failure), pneumonia, acute lung injury, sepsis, and death. In addition, all items in the
drug insert and all events associated with transfusion.
Treatment or Action Taken:
For each adverse event, the site investigator will record
whether an intervention was required:
• Intervention: Surgery or procedure
• Other Treatment: Medication initiation, change, or discontinuation
• None: No action taken
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Outcome of Event:
Finally, the site investigator will record the clinical outcome of
each adverse event as follows:
• Death
• Recovered and the subject returned to baseline status
• Recovered with permanent sequelae
• Symptoms continue
8.4.2
Time Period for Adverse Events
For purposes of this study, adverse events will be recorded for the period following
randomization through hospital discharge or 7 days (whichever comes ﬁrst). Events that
occur prior to onset of study drug administration will not be considered adverse events.
These events will be recorded as baseline conditions. Events that occur following hospital
discharge will not be recorded. Adverse events will be followed until resolution or hospital
discharge, whichever is earlier.
8.4.3
Data Collection Procedures for Adverse Events
After subject randomization, all adverse events (including serious adverse events), whether
anticipated or unanticipated, will be recorded according to the date of ﬁrst occurrence,
severity, and their duration, as well as any treatment prescribed. Any medical condition
present at the time of randomization, recorded in the subject’s baseline history at study
entry, which remains unchanged or improves, will not be recorded as an adverse event at
subsequent evaluations. However, worsening of a medical condition that was present at
the time of randomization will be considered a new adverse event and reported.
Abnormal laboratory values that are clinically signiﬁcant will be recorded as adverse
events and the site investigator will assess the severity and relationship to the study.
Laboratory values that are abnormal at the time of randomization and that do not worsen
will not be recorded as adverse events.
Because severe trauma is associated with a large number of laboratory abnormali-
ties, for purposes of this study, abnormal laboratory values will be recorded as adverse
events when the severity grade is grade 2 or higher on the Common Terminology Criteria
for Adverse Events v4.0 (CTCAE). Grade 1 laboratory abnormalities, if expected as
described earlier, do not need to be recorded as adverse events. It is not necessary to
record abnormal laboratory results for those tests included in the Schedule of Evaluations
because all values for these parameters will be collected. If an abnormality of a laboratory
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parameter is considered to be serious by the site investigator, however, it will be necessary
for the site to record and report the event as an SAE.
Adverse events will be coded using the MedDRA coding vocabulary. Coding will be
done centrally at the Data Coordinating Center because this requires speciﬁc training.
8.4.4
Unanticipated Problems (UP)
Unanticipated problems (UP) are deﬁned as incidents, experiences, or outcomes that are
unexpected, related to participation in the study, and suggest that the research places
subjects at a greater risk of harm than was previously known or recognized.
The site investigator will report unanticipated problems to the Data Coordinating
Center within 24 hours. A detailed completed report will be required to be sent to
the Data Coordinating Center within 3 working days of the event. After receipt of the
complete report, the Data Coordinating Center will report these unanticipated problems
to the NHLBI Program Oﬃcial or Project Oﬃcer in an expedited manner (within 24
hours).
In accordance with local IRB requirements, the site investigator may be required
to report such unanticipated problems to the IRB in addition to notifying the Data
Coordinating Center.
In the event that the medical monitor believes that such an event warrants emergent
suspension of enrollment in the trial, and NHLBI staﬀcannot be reached expeditiously,
the Data Coordinating Center will notify the principal investigators (Drs. Nishijima,
Kuppermann) and all site investigators to cease enrollment in the trial. Resumption of
enrollment will not occur without consent of the NHLBI staﬀafter discussion with the
DSMB.
8.4.5
Monitoring Serious Adverse Events
The Principal Investigator of the Data Coordinating Center (Dr. Dean) will act as the
medical monitor for this study. If Dr. Dean is unavailable, a qualiﬁed physician will be
designated to fulﬁll this function.
Site investigators and/or research coordinators will report serious adverse events to the
Data Coordinating Center within 24 hours. A detailed completed report will be required
to be sent to the Data Coordinating Center within 3 working days of the event, and the
medical monitor will assess all serious adverse events reported from site investigators.
For each of these serious adverse events, the site investigator will provide suﬃcient
medical history and clinical details for a safety assessment to be made with regard to
continuation of the trial. The medical monitor will sign each SAE report after review.
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All SAE reports will be retained at the Data Coordinating Center, and all SAE reports
will be available for review by DSMB members and NHLBI staﬀ.
In the unlikely event that the medical monitor believes an unexpected and study-
related SAE warrants emergent cessation of enrollment in the trial, NHLBI staﬀand
the DSMB chairperson will be immediately consulted. If these individuals concur with
the judgment of the medical monitor, or if the NHLBI staﬀand the DSMB chairperson
cannot be reached expeditiously, the Data Coordinating Center will notify the principal
investigators (Drs.Nishijima, Kuppermann) and all site investigators to cease enrollment
in the trial. Resumption of enrollment will not occur without consent of the NHLBI staﬀ
after discussion with the DSMB.
In accordance with local IRB requirements, the site investigator may be required to
report such events to the IRB in addition to notifying the Data Coordinating Center.
After notiﬁcation of the NHLBI Program Oﬃcial or Project Oﬃcer, and the DSMB
chairperson, of serious, unexpected, and study-related adverse events or unanticipated
problems (UP), decisions will be made whether to continue the study without change,
and whether to convene the entire DSMB for an emergent meeting. If a decision is made
to suspend enrollment in the trial, this will be reported to the principle investigators (Drs.
Nishijima, Kuppermann) and all clinical investigators, who will be instructed to report
this to their local IRB.
The DSMB will review all adverse events (not necessarily serious, unexpected, and
study-related) during scheduled DSMB meetings. The Data Coordinating Center will
prepare a Summary Report of Adverse Events for the DSMB meetings, classiﬁed with
the MedDRA coding system.
8.4.6
Follow-up of Serious, Unexpected and Related Adverse Events
All serious, unexpected and related adverse events that are unresolved at the time of the
subject’s termination from the study or discharge from the hospital will be followed by
the Clinical Center investigators until the events are resolved, subject is lost to follow-up,
the adverse event is otherwise explained, or has stabilized.
9
Study Training
9.1
Study Training
A formal training program for investigators and research staﬀwill be held prior to
the start of enrollment. The training program will cover regulatory topics and Good
Clinical Practice. The training will also provide in depth explanations regarding study
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procedures, clinical care, adverse event reporting, data entry procedures, quality assurance,
site monitoring, and the informed consent process. A manual of operations will be
provided to each investigator prior to the start of enrollment. The manual will detail
speciﬁc information about the study procedures, regulatory information, safety reporting,
and other necessary information. Updates and revisions to the manual will be made
available electronically. The Data Coordinating Center, in collaboration with the principal
investigators (Drs. Nishijima, Kuppermann), will be the main contact for study questions.
Follow-up assessments including PedsQL and GOS-E Peds, as well as digit span testing,
will be performed by qualiﬁed staﬀat the University of California, Davis.
An in-person meeting will be held to review study activities, study workﬂow, and data
entry procedures. Each site investigator should instruct the group of ED physicians at
their home institutions about the study, and serve as local advocates and champions for
the study and answer questions as they arise. Throughout the study, the study team will
also have telephone conference calls, webinars, and in-person meetings to update on study
progress and provide on-going training.
9.2
PECARN Network Involvement
This proposed pilot study of TXA for children with hemorrhagic torso injuries and
traumatic intracranial hemorrhage will be completed within PECARN.86
PECARN is the ﬁrst and only federally-funded pediatric emergency medicine research
network in the United States, initially funded in 2001 through cooperative agreements
between academic medical centers and the Health Resources Services Administration /
Maternal and Child Health Bureau / Emergency Medical Services for Children Program
(HRSA / MCHB / EMSC). PECARN was created to address barriers to research in
emergency medical services for children (EMSC), including the lack of an infrastructure.
PECARN conducts high-priority, multi-institutional research on the prevention and
management of acute illnesses and injuries in children. Currently PECARN is comprised
of 6 research nodes, an EMS research node containing 3 EMS aﬃliates, and a DCC. Each
of the 6 research nodes has 3 hospital ED aﬃliates and one EMS aﬃliate. Overall, the
PECARN EDs serve approximately 1.1 million acutely ill and injured children annually
in the US.
The PECARN network is governed by a Steering Committee that formulates and
monitors policies and procedures guiding all research activities and reviews and approves
research proposals. All major scientiﬁc decisions are made by majority vote. Subcommit-
tees, including the Protocol Review and Development Subcommittee (PRADs), the Grant
Writing and Publications Subcommittee (GAPS), the Feasibility and Budget Subcom-
mittee (FAB), and the Quality, Safety, and Regulatory Aﬀairs Subcommittee (QUASI)
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carry out speciﬁc tasks identiﬁed by the Steering Committee. This pilot project has been
reviewed and approved by PECARN.
10
Regulatory Issues
10.1
Food and Drug Administration
This trial is being conducted under an Investigational New Drug application approved by
the Food and Drug Administration (Investigational New Drug application #128206). The
clinical investigator at each participating site will complete a Form FDA 1572, “Statement
of Investigator.”
10.2
Health Insurance Portability and Accountability Act
Data elements collected include the date of birth and date of admission. Prior to statistical
analyses, dates will be used to calculate subject age at the time of the study events. The
ﬁnal data sets (used for study analyses and archived at the end of the study) will be
de–identiﬁed, and will exclude these speciﬁc dates.
Data elements for race, ethnicity, and gender are also being collected. These demo-
graphic data are required for Federal reporting purposes to delineate subject accrual by
race, ethnicity, and gender.
For purposes of the DCC handling potential protected health information (PHI) and
producing the de–identiﬁed research data sets that will be used for analyses, all study sites
have been oﬀered a Business Associate Agreement with the University of Utah. Copies of
executed Business Associate Agreements are maintained at the DCC.
10.3
Inclusion of Women and Minorities
There will be no exclusion of subjects based on gender, race, or ethnicity.
10.4
ClinicalTrials.gov Requirements
This trial will be registered at ClinicalTrials.gov in accordance with Federal regulations.
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10.5
Retention of Records
For federally funded studies subject to the Common Rule, records relating to the research
conducted shall be retained for a period of 2 years following the date a marketing
application is approved for the drug for the indication for which it is being investigated;
or, if no application is to be ﬁled or if the application is not approved for such indication,
until 2 years after the investigation is discontinued and FDA is notiﬁed. Completion of the
research for this protocol should be anticipated to include planned primary and secondary
analyses, as well as subsequent derivative analyses. Completion of the research also entails
completion of all publications relating to the research. All records shall be accessible
for inspection and copying by authorized representatives of the regulatory authorities at
reasonable times and in a reasonable manner [45 CFR §46.115(b)]. In such cases where
local regulations require that records be kept longer than the Federal Regulations require,
records will be retained for the duration required by the local regulations.
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