Clinical trial NCT02320669
Conditions: Congenital Heart Defects
Sponsor: Seattle Children's Hospital
Start date: 2014-11-01; Completion date: 2019-10-01
Enrollment: 220 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study to determine the safety and efficacy of liothyronine sodium/triiodothyronine (Triostat), a synthetic thyroid hormone, when given to infants with congenital heart disease during cardiopulmonary bypass surgery. Funding Source - FDA OOPD.

Detailed description:

Arms: arm 1: Active Medication - Synthetic Thyroid Hormone arm 2: Placebo Control
Interventions: intervention 1: Triostat intervention 2: Placebo
Intervention descriptions: intervention 1: Bolus of Triiodothyronine followed by infusion for 48 hours intervention 2: Bolus of Placebo followed by infusion for 48 hours

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 of 25 
 
This document contains study protocol and statistical plan for  
 
14798 NCT02320669 Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary 
Bypass (TRICC-2) 
 
 


Page 2 of 25 
 
Seattle Children’s Hospital 
 
 
 
 
 
 
  
 
TRICC-2:  TRIIODOTHYRONINE SUPPLEMENTATION IN INFANTS 
UNDERGOING CARDIOPULMONARY BYPASS 
IND 55367 
 
A randomized, double blind, placebo controlled study of the effects of Triiodothyronine in Infants Undergoing 
Cardiopulmonary Bypass 
 
Research Study Protocol 
Sponsor-Investigator: 
Michael A. Portman, MD 
Department of Pediatrics/ Cardiology 
1900 9th Avenue 
Seattle, WA 98101 
(206) 987-1014  
 
 
Study Product: 
Triiodothyronine (trade name: Triostat) 
 
Date:  
 
 
30 September 2015 
Amendment #:  
 
4 
 
Signatures: 
 
_______________________________________  
 
 
 
_________________ 
Study Sponsor/Study Principal Investigator  
 
 
 
Date 
 
________________________________________ 
 
 
 
_________________ 
Site Principal Investigator 
 
 
 
 
 
 
Date 
CONFIDENTIAL 
This document is confidential and the property of the Children's Hospital and Regional Medical Center.  
No part of it may be transmitted, reproduced, published, or used by other persons without prior written 
authorization from the study sponsor-investigator. 


Page 3 of 25 
 
 
Contents 
List of Abbreviations .......................................................................................................................................... 4 
Significance ....................................................................................................................................................... 6 
Study Design and Innovation ............................................................................................................................. 8 
Study Population ............................................................................................................................................... 8 
STRATIFICATION DESIGN .............................................................................................................................. 9 
Justification for Age Strata ............................................................................................................................. 9 
Primary Clinical Endpoint ................................................................................................................................. 10 
Secondary Endpoints ................................................................................................................................... 11 
Triostat Dosing ................................................................................................................................................ 13 
Study Conduct and Procedures ....................................................................................................................... 14 
Study Recruitment and Screening ................................................................................................................ 14 
Early Withdrawal of Subjects ........................................................................................................................ 14 
Inclusion/Exclusion Criteria .......................................................................................................................... 14 
Schedule of Events ...................................................................................................................................... 15 
Data to Capture from Subject Medical Record ................................................................................................. 17 
Participating Centers and Eligible Population .................................................................................................. 17 
Blinding and Randomization ............................................................................................................................ 17 
Data Recording ............................................................................................................................................... 18 
Statistical Analysis ........................................................................................................................................... 18 
Safety .............................................................................................................................................................. 19 
Adverse Event (AE) Reporting ......................................................................................................................... 19 
Compliance and Monitoring ............................................................................................................................. 20 
Data Management ........................................................................................................................................... 21 
Data Monitoring Committee ............................................................................................................................. 21 
Appendix 1: Listing of Expected AE’s .............................................................................................................. 22 
Citations .......................................................................................................................................................... 24 
 
 
 
 
 
 


Page 4 of 25 
 
List of Abbreviations 
AE 
Adverse Event 
CAVC 
Complete Atrioventricular Canal 
CICU 
Cardiac Intensive Care Unit 
CoA 
Coartctation of Aorta 
COV 
Closeout Visit 
CPB 
Cardiopulmonary Bypass 
CRF 
Case report forms 
CRO 
Clinical Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
DSC 
Delayed Sternal Closure 
ECMO 
Extracorporeal Membrane Oxygenation 
FDA 
US Food and Drug Adminstration 
HIPAA 
Health Insurance Portability and Accountability Act 
HLHS 
Hyperplastic Left Heart Syndrome 
HLV 
Hypoplastic Left Ventricle 
ICU 
Intensive Care Unit 
ICU-LOS Intensive Care Unit Length of Stay 
IMV 
Interim Monitoring Visit 
IND 
Investigational New Drug Application 
ITT 
Intention to Treat 
LACH 
Los Angeles Children’s Hospital 
LPCH 
Lucille Packard Children’s Hospital 
NIH 
National Institutes of Health 
NR  
Not Responsible 
OOPD  
Office of Orphan Product Development 


Page 5 of 25 
 
PHN 
Pediatric Heart Network 
QoL 
Quality of Life 
R-ICU 
Readiness for ICU Discharge 
SAE 
Serious Adverse Event 
SCH 
Seattle Children’s Hospital 
SIV 
Site Initiation Visit 
SVC-PA 
Superior Vena Cava to Pulmonary Artery Shunt 
T3 
Triiodothyronine 
T4 
Thyroxine 
TAPVD 
Total Anomalous Pulmonary Venous Drainage 
ToF 
Teratology of Fallot 
TGA 
Transposition of Great Arteries 
TSH 
Thyroid Stimulating Hormone 
TTE 
Time to Extubation 
VSD 
Ventricular Septal Defect 
 
 
 


Page 6 of 25 
 
Significance   
Congenital heart disease occurs in approximately 32,000 infants per year. The American Heart Association 
estimates that 300,000 children under age 21 have a congenital heart defect, and approximately thirty-eight 
percent of these will have one or more surgical procedures.  This cohort of infants undergoing cardiac surgery 
represents an orphan disease population by NIH and FDA definitions.  Over the past 20 years increasing 
numbers of patients have undergone cardiopulmonary bypass for correction of congenital heart defects and or 
palliation of single ventricle type anatomy.  Technical advances have been made in these surgical procedures.  
However, progress has been limited with regard to pharmacological management of infants during the 
postoperative period.  Rapid extubation strategies have been applied at many centers in older infants 
and children2, 3 in attempts to reduce morbidity associated with prolonged intubation.  However cardiac 
surgery and cardiopulmonary bypass in neonates and young infants still results in long periods in the 
cardiac intensive care units.  Long CICU stay is often due to prolonged time on mechanical ventilation 
with associated acute and long term morbidities.  Relatively few randomized clinical trials have evaluated 
agents provided to these infants after cardiopulmonary bypass.  The recent Triiodothyronine Supplementation 
in Infants and Children Undergoing Cardiopulmonary Bypass (TRICC) clinical trial performed under IND # 
55367 demonstrated a fairly straightforward and safe pharmacological approach to reducing mechanical 
ventilation time5.  However, further data is required in order to apply for the labeling change for triiodothyronine 
(liothyronine), which would impact current standard of care.   
 
Cardiopulmonary Bypass disturbs thyroid hormone homeostasis in adults and children6, 7.  Initially, these 
disturbances were considered physiological adaptations to surgical stress, which would modify oxygen 
consumption.   However, emerging evidence shows that inflammation initiated by CPB circuits inhibits the 
thyroid hormone axis at multiple levels 8 9 10.  Thus, marked and persistent depression of circulating hormones 
after CPB is directly caused by this procedure which stimulates cytokine storm.   Circulating triiodothyronine 
levels related directly to clinical outcome in many studies in both adult and pediatric populations6, 7.  Several 
manipulations in the CPB circuitry such as addition of ultrafiltration as well as steroids have been used to 
reduce the impact of this inflammatory response with variable overall effects11, 12.   Accordingly, specific 
therapy targeted at correcting disturbances in thyroid hormone homeostasis is warranted.  Preclinical trials in 
animal models show that triiodothyronine supplementation improves cardiac function after reperfusion13.  The 
mechanisms of action still require elucidation.  Recent studies in our laboratory indicate that thyroid hormone 
modulates substrate utilization to provide increased energy for contractile function13.  Controlled clinical trials 
performed in adults undergoing CPB have shown that T3 supplementation produces remarkably positive 
effects on clinical outcome parameters7, 14, 15.  In particular, T3 supplementation reduces atrial excitability in the 
postoperative period, manifested by reduced incidence of atrial fibrillation in the treated study population14.  
Despite these positive clinical outcome parameters triiodothyronine supplementation has not gained standard 
of care status in the adult population undergoing cardiopulmonary bypass.  The reasons for this lack of general 
acceptance are unclear but may relate to the generic status of triiodothyronine (marketed as liothyronine) and 
absence of a particular champion pharmaceutical company. 


Page 7 of 25 
 
Infants exhibit particularly profound abnormalities in 
thyroid hormone homeostasis, which will be detailed in 
preliminary data.  Unexplained myocardial stunning 
occurs after CPB which relates directly to thyroid 
hormone levels, and prolongs time on mechanical 
ventilation after surgery.  Data from several small clinical 
trials of T3 supplementation in general populations of 
children undergoing surgery for congenital heart defects 
(age: 0 – 18 years) suggested that T3 supplementation 
might be helpful in postoperative period1, 16, 17.   These 
results should be considered in the context of the state of 
clinical trials and the use of drugs for children undergoing 
cardiopulmonary bypass.  Approximately 80% of drugs 
used in children are not approved for pediatric indications.  
Most of the drugs used routinely in the intensive care unit 
have not been evaluated via randomized clinical trials in a 
pediatric population.  In fact, careful review of the literature 
shows evidence that some of these agents, for example 
dopamine and dobutamine, have poor benefit to safety 
ratios.  Dobutamine and dopamine are highly 
arrhythmogenic18.  Only milrinone has been evaluated in a  
controlled clinical trial in children19.   Although this drug 
has received labeling status by FDA and appears safe, the 
data supporting its use are weakened by a composite 
outcome parameter that has never been validated.  
 
The Triiodothyronine during Cardiopulmonary bypass 
in Infants and Children (TRICC) clinical trial 
tested the hypothesis that triiodothyronine 
supplementation reduces time on mechanical 
ventilation after cardiopulmonary bypass.   The 
FDA Office of Orphan Product Development 
funded the trial. The double blind, placebo 
controlled, multi-center study randomized 
almost 200 children under the age of 2 years, 
making it the largest drug trial performed in this 
population5.   Triiodothyronine supplementation 
did not significantly influence the primary 
clinical endpoint, the time to extubation, in the 
entire study cohort.   However, we, the 
investigators, planned a priori analyses by age.  
We determined that the T3 effect is not 
heterogeneous over all ages from birth to 2 
years, as evidenced by a significant treatment 
by age interaction when the study population was 
divided at the median age of 5 months.    Post-hoc  
analyses (Figure 1 and 2) revealed that T3 
Figure  2.  TRICC trial data.  Kaplan-Meier curves for subjects < 5 
months age and subjects age > 5 months. (Statistics by Cox 
Proportional Hazards):   Hazard Ratio for the Triostat group among 
patients < 5 months was 1.72 (p=0.0216), and for > 5 months 
0.60 (p = 0.0220).  Below the graph are N at risk, number of 
extubations, (% intubated). 
Figure 1.  TRICC trial data. Relationship between time to 
extubation and age in months (top panel).  Smoothed 
regression lines for Placebo and Triostat groups converge 
just above 5 months of age.   Median TTE with 
confidence intervals is shown by age groups (lower 
panel). 


Page 8 of 25 
 
substantially benefited patients less than 5 months of age by reducing the median time to extubation by 43 
hours when compared to placebo (T3-treated median-55 hours; 95% CI, 44–92;  Placebo 98 hours; 95% CI, 
71–142). The study linked the positive clinical outcome to two potential mechanisms.  First, T3 treatment 
improved cardiac function as assessed by echocardiographic parameters.  Second, T3 supplementation 
promoted a decrease in inotropic agent use even though cardiac function improved (Figure 3).  In addition to 
these results, the trial demonstrated the overall safety of T3 supplementation.  TRICC provided data which can 
and likely has impacted care in these very young patients undergoing surgery for congenital heart diseases.  
However, the FDA denied application for a labeling change to include this indication as we did not demonstrate 
efficacy in the entire trial cohort, and the analysis by age was not a pre-specified primary endpoint (0 – 2 years 
of age was the prespecified primary endpoint).  The FDA would not consider a Triostat label change for cardiac 
surgery based on post-hoc analyses of a specific subgroup. Nor would they consider change in labeling 
regarding safety without demonstrating efficacy in the entire cohort.  Accordingly, the FDA suggested that 
another prospective trial in the specific age group with potential to benefit from treatment was necessary to 
apply for a labeling change.  Thus, we propose performing a second trial in infants less than 5 months of age. 
The primary efficacy endpoint will be the affect of T3 supplementation on all patients less than 5 months of 
age. Randomization will be stratified based on age (< or ≥ 4 weeks).   The age strata will be considered 
separately as secondary analyses.   
 
 
 
Study Design and Innovation 
We will determine if triiodothyronine supplementation after 
cardiopulmonary bypass reduces time on mechanical ventilation 
in infants less than age 5 months.  
Innovation resides in the clinical study design, which will 
capture time to extubation, cardiac intensive care unit (CICU) 
days, discharge feeding tube use, and other endpoints so that 
the results can be evaluated in terms of clinical benefit, resource 
use, and quality of life components. Consideration of this 
treatment strategy from a clinical, cost/value and Quality of Life 
stand-point will show the entire picture.  Based on our TRICC 
results, we expect to find a meaningful effect on TTE, a slight 
decrease in resource use (CICU days), an increase in QoL 
(more discharges on full oral feeds) associated with T3 
supplementation; all for a therapy which has a minimal cost. 
Figure 3.  Diagnosis distribution between age 
groups in TRICC.  First 5 groups are High Risk by 
Aristotle Score > 10.  CoA, infant coarctation; 
TGA, arterial switch for transposition; HLV,  
stage I palliation for hypoplastic left heart; 
TAPVD, total anomalous pulmonary venous 
drainage;  VSD, ventricular septal defect; TOF, 
Tetralogy of Fallot; CAVC, complete 
atrioventricular canal; SVC-PA, superior vena 
cava to pulmonary artery shunt or Glenn.  


Page 9 of 25 
 
Study Population 
The TRICC study identified patients < 5 months as those with the most potential benefit from triiodothyronine 
supplementation.   In TRICC we used Aristotle score to quantify the complexity and risk of the surgical 
procedure.20-22.  High risk was defined as an adjusted Aristotle score greater than 10.  The profile for study 
patients according to this diagnosis stratification is shown in Figure 3.   This figure shows that with increasing 
age, the population shifts towards lower risk categories. From these profiles it is clear that patients less than 5 
months of age have increased risk not only due to younger age but also due to greater surgical complexity.  
The age related findings from the TRICC trial were presented at the Annual Sessions of the American Heart 
Association in 2010.   Physicians in attendance, who care for these children, questioned whether the response 
in neonates differed from older infants. TRICC was not designed to answer this question. 
STRATIFICATION DESIGN 
Accordingly, we have designed TRICC 2 with age strata: less than 4 weeks and greater than or equal to 4 weeks in 
order to have sufficient numbers of younger and older patients to address whether the affect is different in 
neonates. The logic behind 
the stratification is a 
combination of published 
and preliminary data.  
 
Justification for Age 
Strata 
Recently published data 
obtained by the PI in 
collaboration with M. 
Cantinotti et al show that 
infants less than 4 weeks 
old demonstrate 
differences in thyroid 
hormone profile both 
before and after 
cardiopulmonary bypass 
compared to older 
children (Figure 5).  
Although declinations in TSH, T3, 
and T4 are not as profound as 
those in older children, they persist 
longer after CPB, suggesting that 
response to T3 supplementation might be different in neonates < 4 weeks old.   The TRICC trial was not 
powered to perform more detailed age stratification and separate out the neonatal group. However, the 
Kaplan-Meier curves for patients intubated versus time show the logic of the stratification design. This figure 
shows the cumulative percent of patients still requiring intubation versus time in the TRICC study. While the 
patients older than 4 weeks show a substantial benefit, the benefit is reduced in patients less than 4 weeks. It 
is unknown due to the small sample size whether these graphs demonstrate a true difference in the magnitude 
in the effect, or simply show the variability in outcomes in this youngest and sickest population. The 
stratification of TRICC- 2 was designed to enable us to distinguish between the two possibilities.  
Figure 4.  TSH, free T3 and free T4 values for neonates (< 4 weeks, n = 57) in top 
panels and older infants and toddlers (n = 105) in bottom panels.  Neonates show 
lower preoperative values, though postoperative decline in T3 is less severe 4.  


Page 10 of 25 
 
 
 
The target sample size (total 220 enrolled) was calculated to provide statistical power of >80% to 
identify a treatment effect corresponding to a hazard ratio of 1.55 with an overall type I error level of 0.05 (2-
sided).  Patients will be block-randomized by risk and age, with a minimum of 100 patients who are > 4 weeks 
of age. Based on the age distribution in TRICC, we expect about 60% of patients will be greater than or equal 
to 4 weeks, which will provide adequate numbers in each of the age groups. If for some reason high numbers 
of neonates are enrolled, we may cap enrollment of neonates so that at least 100 patients are ≥ 4 weeks. 
Patients will be randomized to T3 or placebo in a 1:1 ratio.  
 
Primary Clinical Endpoint 
Time to extubation (TTE) will be the primary clinical endpoint in this study.  FDA regulators agree that this 
endpoint is appropriate to apply for a labeling change for Triostat.  Studies of children undergoing surgery for 
congenital heart disease conducted at single centers with uniform hospital utilization have shown that 
decreasing TTE results in overall reduced hospital stay and cost 3.   Time to extubation in infants also relates 
to longer term quality of life indicators.  For instance, most congenital heart centers report that the majority of 
these infants demonstrate continuing oral feeding difficulties at discharge.   Between 50 and 60% are 
discharged from the hospital with either full or supplemental feeds through nasogastric tubes or gastrostomy23, 
24  After discharge, nasogastric feeding continues at home with substantial increased cost, and detriment to the 
quality of life of the infants and their parents.   Several studies have reported that prolonged time to extubation 
is the single most important predictor for discharge on nasogastric feeds. 23, 24  This specific quality of life 
indicator, discharge of full oral feeds will be used as secondary endpoint indicator.  
 
Composite endpoints have been used in pediatric intensive care studies with variable and limited success19 1.  
Validity of these composite endpoints is often questioned.  Frequently used endpoints such as time in intensive 
care unit and hospital stay are burdened by variable practice in a multi-center study. Additionally transfers 
require staff availability, which is not always feasible.  For instance, some of the participating centers in the 
TRICC trial discharged patients to home directly from the intensive care unit.   TTE is considered an important 
clinical endpoint and benchmark in pediatric cardiac surgical series.  Mechanical ventilation is an important 
source of anxiety for parents with children in the intensive care unit25 . Furthermore, we successfully detected 
differences in TTE in TRICC, establishing that T3 supplementation affects this endpoint.  Therefore TTE was 
selected as an objective outcome measure for this study.  We recognize this endpoint has limitations, due to 
Figure 5.  TRICC trial data for 2 age groups 
under 5 months old.  For patients <=4 weeks:  
N = 25, Placebo; 25 Triostat.  For patients >4 
weeks: N = Placebo 25, and Triostat 23.   
Though not adequately powered, data suggest 
more potent treatment impact in the older 
patient group.  These data support age 
stratification design in our study.  Data below 
figures reflect median (25,75%tile) 


Page 11 of 25 
 
ambiguity of start and stop time. First, time 0, the start of the intubation period, has been poorly defined in 
multiple analyses evaluating pediatric cardiac surgery.  Start time has been defined as initial time to intubation 
prior to surgery, entrance into the operating room, or surgical completion.  None of these time-points have 
relevance to surgical outcome, and are influenced by factors such as the complexity of the procedure and skill 
of the surgeon.  Therefore, time from aortic cross-clamp removal will be defined as time 0 (start time) because 
under this definition it can be objectively measured. 
 
In TRICC-2, all participating investigators will commit to reducing non-patient related delays in extubation and 
document the time of readiness to extubate along with any reason for delay, if a delay cannot be avoided. For 
the calculation of the primary endpoint, the actual extubation time will be used. It is essential that treating 
physicians are blinded to treatment assignment to prevent bias in deciding appropriate extubation time.  
 
Delayed sternal closure (DSC) is an effective approach to the management of neonates and infants at risk for 
hemodynamic, respiratory, or hemostatic instability early after cardiac surgery 26.  However, DSC is an 
important confounding influence on time to extubation, and must be considered in this study design.   Use of 
DSC varies among institutions but a multi-center retrospective study showed that it contributes to longer length 
of hospital stay and higher postoperative infection rates in patients undergoing stage 1 palliation for hypoplastic 
left heart syndrome (HLHS)27.  At centers involved in the study, surgeons often make the decision for DSC 
prior to operative repair or palliation.   In our own series (SCH) DSC prolongs time to extubation by a median of 
2.5 days in HLHS patients compared to patients with standard chest closure, yielding a bimodal distribution for 
time to extubation.   We will adjust for whether DSC actually occurs in the primary analysis Cox Proportional 
Hazards Model.  
 
Secondary Endpoints 
FDA regulators suggested that mortality and/ or additional morbidity parameters would provide important 
supportive data. However, mortality in this population is extremely low, and generally caused by factors which 
would not be improved by pharmacological therapy, such as surgical mishaps, and extremely high risk surgery.   
Furthermore, with mortality rate at 5.3% in placebo group from TRICC and 3% in treatment group, our study 
would require a several fold increase in sample size to be adequately powered. The consensus of ICU 
physicians at the 3 centers participating in this trial is that extubation and removal from the ventilator is the 
primary acute goal for these patients.    Parent groups also report that extubation is the most important 
parameter.  We have evaluated adverse events as potential morbidity endpoints, but these are numerous, 
diverse, subjective, and therefore are not suitable for a composite endpoint.   Hospital length-of-stay was 
considered as a potential outcome parameter;   however this is influenced by center-specific protocols, 
readiness of family to have the child come home, and other variables which are clearly beyond the effect of T3.  
ICU length-of-stay (ICU-LOS) is used universally as an outcome parameter in adult and pediatric studies.  
Studies employing this outcome parameter are generally based on a large population, which is necessary due 
to the non-patient related issues and events.  We have evaluated ICU-LOS as a potential secondary endpoint.  
The median ICU- LOS in TRICC patients < 4 weeks old was 7.5days (IQR 6-14) with Triostat, and 8.5 days 
(IQR 7-13.5) with Placebo.  The values for patients >4 weeks were 4.5 days (IQR 4.0-9.0) with Triostat and 7 
days (IQR 4.0- 16.5) Placebo. T3 supplementation may influence ICU-LOS among the older patients, although 
less likely to influence this parameter in the younger neonatal group.   
 
We will use ICU-LOS as a secondary endpoint.  This will not eliminate problems related to step-down unit 
availability etc.   We therefore introduce another secondary endpoint, which is a composite value similar to that 
used by Mackie et al.   This endpoint will be termed “ready for ICU discharge”, and defined as the number of 


Page 12 of 25 
 
hours from termination of cardiopulmonary bypass to readiness for ICU discharge.   The intensivists and 
investigators agreed to record this endpoint (R-ICU) when both of the following parameters are reached: 1) all 
inotropic drugs terminated; 2) patient extubated and in no respiratory distress, only oxygen supplied by nasal 
cannula or mask; 3) If on high flow nasal cannula Max O2 4L (0-90d old) or 6L (91d-2y), FiO2 ≤ 50%:   
 
As noted previously, delayed TTE is a direct predictor of “oral feeding difficulty” resulting in hospital discharge 
on alternate feeding modes such as nasogastric tube23, 24.  Discharge with nasogastric tube reduces quality of 
life for infants and families.  Therefore we will use discharge on full oral feeds as a secondary quality of life 
end point.  
 
In order to assess cardiac endpoint parameters we will use Low Cardiac Output Syndrome (LCOS) as 
another secondary endpoint.  This assessment will be competed on a separate CRF for LCOS for the first 36 
hours after ICU admission and will include 1) identifying clinical signs/symptoms present in LCOS; 2) 
identifying all interventions involved in the treatment of LCOS; 3) Pharmacologic Assessment of 
inotropes/vasopressures 
 
Summary of secondary endpoints 
1) ICU-LOS 
2) R-ICU  
3) Discharge on Oral feeds 
4) LCOS 
5) Mortality* 
6) Mortality and/or mechanical circulation (ECMO)* 
• 
*The PI anticipates that the study is inadequately powered to detect differences in these endpoints 
between treatment groups, but they were suggested by the FDA regulators.  
7) Time to sternal closure for patients with delayed surgical closure 
 
Echocardiography was performed as part of the protocol in the TRICC trial.  Echocardiography, as noted 
previously, established a treatment effect on cardiac contractile function.   However, echocardiography 
parameters were secondary endpoints.  Performance of echocardiography burdened the study with regards to 
enrollment due to staffing issues (sonographer unavailability at protocol time points) and is prohibitively 
expensive at U.S. centers.   We considered the benefit of echocardiography as part of the protocol versus the 
cost.  Accordingly, echocardiography will not be performed as part of protocol, although performance of the 
study will not impact standard of care studies. A previous review observed this point, and suggested that we 
use data obtained for clinical purposes outside of the protocol.  However, these evaluations are ordered based 
on clinical necessity.  As such the sickest patients might have echo data and the others would not, creating a 
biased sample.   
 
 
 
 
 
 
 
 
 
 
 
 


Page 13 of 25 
 
Triostat Dosing 
Triostat ® (liothyronine sodium injection), 10µg/mL, 1mL vial is 
currently distributed by JHP Pharmaceuticals. Supplementation 
elevated total triiodothyronine levels in the TRICC trial as noted 
in Figure 6.  For TRICC the dosing strategy was 0.4µg/kg prior 
to CPB and immediately after cross-clamp release and 0.2µg/kg 
every 3 hours thereafter for 3 doses, thereby supplying a total 
1.4µg/kg over an approximate 10 hour period.   This strategy 
was effective in patients less than 5-months oldbut did not provide 
steady-state levels, and maintained levels above the placebo 
group for only 24 hours, by 24 hours levels in both placebo and 
treatment groups were well below baseline. Additionally, the 
strategy produced substantial peaks in serum T3 levels, although 
these were not associated with adverse events.  The primary 
reason for bolus was concern regarding liothyronine 
incompatibility with other drugs, and the limited number of 
infusions available in these small patients.  These have been 
obviated with newer types of lines and infusion pumps.   
Liothyronine is compatible with drugs given in the ICU.   Prior 
studies have used liothyronine (Triostat) infusion in this 
vulnerable population with no drug incompatibility reported.  
Data from the TRICC trial and a smaller trial performed by our 
Lucille-Packard co-investigator support bolus dosing followed 
by infusion. Dr. Stephen Roth published pharmacokinetic data 
from a series of neonates undergoing surgical procedures 
requiring CBP.   In his study, Triostat infusion (0.06 µg/kg/hour) 
initiated immediately after terminating CPB prevented total T3 
decline to below normal levels in many but not all patients.  The infusion produced optimum levels within the 
normal range by 24 to 48 hours (n = 23).   These data strongly support a composite protocol using initial bolus 
to prevent early decline in T3, and then followed by the established maintenance infusion.  
 
Accordingly, we will use a strategy with an initial loading dose 0.4µg/kg validated in TRICC after cross clamp 
removal or similar time point surrogate followed by an infusion totaling approximately 3 µg/kg infused as 0.06 
µg/kg/hr for 48 hours or until extubation in the CICU, whichever time is shorter (validated by Mackie et al, 
(Stephen Roth)1.  This dose is intended to prevent the initial decline and maintain relatively steady-state levels 
well within the normative range for the 48-hour time period; data from TRICC as well as our preliminary data in 
infants younger than 4 weeks show persistence of the hypothyroid period extending through 48 hours.    
 
 
 
 
Figure 6.  A. Dosing strategy in TRICC trial 
raised total T3 levels with peak at 1 hour with 
slow decline reaching placebo group levels 
after 24 hours.  Because of persistent low levels 
shown below for at least 72 hours and in Figure 
5, the new trial strategy is to extend T3 infusion, 
supported by data in B published by 
collaborator Stephen Roth 1.   


Page 14 of 25 
 
 
Study Conduct and Procedures 
 
Study Recruitment and Screening 
Subjects will be recruited from admissions at participating centers scheduled to undergo a cardiac procedure 
requiring CPB.  Potential subjects will be screened for study suitability by the research staff in cooperation with 
the clinical care team.  A screening log will be kept at each site.  If the family shows interest in the study, they 
will undergo informed consent procedures which will be conducted by the research team.  The study will be 
described verbally to the patient and family.  After the introduction and description of the study, the family will 
be given adequate time to read and review the written consent forms.  Time will be allotted for questions and 
additional discussion, if necessary.  Family friends, relatives or additional support persons (at the request of 
the parent/guardian) may also be present to hear and read what is being asked of the family. 
Early Withdrawal of Subjects 
When and how to withdraw subjects: Subject may be withdrawn from the study prior to the expected 
completion of that subject for health, logistical, or personal reasons (i.e. serious adverse events, subject 
consent withdrawal, disease progression, etc.).  No safety consequences are anticipated with early withdrawal 
from the study since Triostat is adjunctive therapy. 
Data Collection and Follow-up for Withdrawn Subjects: Subjects who receive study medication and are 
withdrawn will be followed through the duration of the study for that subject.  Subjects who withdraw consent 
will be asked if study data can be collected for the duration of the study.  Subjects who completely withdraw 
consent and do not wish to have further data collected will not be followed past the point of withdrawal of 
consent. 
Emergency Blind Breaking: At the beginning of the study, each site will be instructed on the method for 
emergency blind-breaking.  Blinding codes may be broken in emergency situations if this is required for clinical 
management.  The Principal Investigator at the site will contact Dr. Portman to assess the necessity for un-
blinding.  In the unlikely event that Dr. Portman is unreachable, the site Principal Investigator will be 
responsible for making the decision to unblind the patient.  The study investigator will instruct the participating 
site pharmacy to break the blind to the treating physician only.  The study investigators at the site as well as 
Dr. Portman are to remain blinded to protect the integrity of the data. 
Inclusion/Exclusion Criteria 
Inclusion Criteria: 
1.  Informed Consent obtained 
2. Male and female patients <5 months (152 days) of age 
3. Patients undergoing cardiopulmonary bypass 
Exclusion Criteria: 
1.  Known thyroid disease (Down Syndrome is not an exclusion criterion unless the patient has thyroid disease) 
2. Trisomy 13 and 18 


Page 15 of 25 
 
3. Prolonged preoperative ventilator support which would not be impacted by cardiac surgery (Lung disease: 
bronchopulmonary dysplasia, hypoplastic lungs associated with diaphragmatic hernia) 
4. Any other condition as determined by the PI causing prolonged ventilator support which is unlikely to 
respond favorably to cardiac surgery 
5. Prior participation in the clinical trial 
Schedule of Events 
1. Prior to Surgery 
a. Informed Consent 
b. Inclusion/Exclusion 
c. PK/thyroid hormone Blood Sample 
d. Demographics 
2. Prior to first bolus of Triostat/Aortic Cross Clamp 
a. PK/thyroid hormone Blood Sample 
3. Triostat Bolus/Release of Aortic Cross Clamp 
a. Triostat Bolus – 0.4µg/kg 
b. Triostat infusion started – 0.06 µg/kg/hr 
4.  6 hours post 1st Triostat bolus 
a. PK/thyroid hormone Blood Sample (±1hour) 
b. Echo 
5. 12 hours post 1st Triostat bolus 
a. PK/thyroid hormone Blood Sample (±1hour) 
b. Record a charted Blood Pressure measurement (±1 hour) 
6. 24  hours post 1st Triostat bolus 
a. PK/thyroid hormone Blood Sample (±1hour) 
b. Record I/O for previous 24 hours 
c. Echo 
7. 48 hours 
a. Record I/O for previous 24 hours 
b. Stop Triostat infusion (either here or at extubation, whichever is sooner) 
8. 72  hours post 1st Triostat bolus 
a. PK/thyroid hormone Blood Sample (±1hour) 
b. Record I/O for previous 24 hours 
c. Echo 
9. 30 day follow-up (Chart Review – to be completed 30 days post stoppage of medication) 
a. AE assessment 
b. Vital Status 
c. Feeding Status 
10. Endpoints: Date and time to be recorded for the following (if applicable) 
a. Primary 
i. Extubation 
b. Secondary 
i. ICU discharge/ready for ICU discharge 
ii. Feeding tube stop time 
iii. Time of sternal closure 
iv. Death (if applicable) 
v. ECMO start (if applicable) 


Page 16 of 25 
 
11. Timepoints to be recorded 
 
a. Aortic Cross Clamp time 
b. Release of Aortic Cross Clamp time 
c. ICU discharge time/ready for ICU discharge time 
d. Feeding tube stop time 
e. Time of sternal closure 
f. Death (if applicable) 
g. ECMO start (if applicable) 
 
• 
The aortic cross clamp removal time used should be the first instance of cross clamp removal.  The 
cross clamp may be removed and reclamped, however the schedule of events is timed off of the first 
cross clamp removal time. 
• 
Blood draw windows apply only if there are vascular lines in place that can be drawn from.  In the event 
that lines have been discontinued, it is acceptable to have study samples drawn at the time of the 
closest clinical draw (non study-driven blood draw) to a timepoint.  Missing or late blood draws due to a 
lack of a vascular line or no timely clinical blood draws will not be considered a deviation.  This most 
likely applies to the 72 hour blood draw timepoint. 
• 
The medication bolus and infusion will be given in the 1 hour window after cross clamp removal. 
• 
The medication infusion will be stopped in a ± 2 hour window after either extubation or 48 hours after 
cross clamp removal, which ever comes first. 
• 
Concomitant medications include medications taken in the 4 weeks prior to hospitalization and continue 
through 30 day follow-up discharge of the index hospitalization. 
• 
Capture of hemodynamic parameters & lactate levels will be captured as part of standard of care 
measurements and will not be driven by the protocol.  Hemodynamic parameters will be captured for 
the duration of the study  
• 
Echoes are done per Standard of care and are not driven by the study.  While the schedule of events 
specifies an echo at 6, 24, and 72 hours, it is not a deviation if one of these is missed or late.  The echo 
most closely correlating to this timing will be used at each timepoint. 
• 
All PK/thyroid hormone samples taken require 2ml of blood in a red top tube at each timepoint. 
 
 
Prior to Surgery 
Release of Aortic Cross 
Clamp 
6 hours 
12 hours 
24 hours 
48 hours 
72 hours 
 
30d f/u (Chart Review) 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
Blood Sample 
X 
X 
X 
X 
X 
 
X 
 
Demographics 
X 
 
 
 
 
 
 
 
Triostat Bolus 
 
X 
 
 
 
 
 
 
Start Triostat Infusion 
 
X 
 
 
 
 
 
 
Stop Triostat Infusion 
 
 
 
 
 
X 
 
 


Page 17 of 25 
 
Echo 
 
 
X 
 
X 
 
X 
 
Intake/Output (I/O) 
 
 
 
 
X 
X 
X 
 
f/u - Chart Review 
 
 
 
 
 
 
 
X 
Data to Capture from Subject Medical Record 
Various data points are recorded on each subject as a part of routine clinical care.  Some of those data points 
are desired to be captured in the TRICC2 study.  Accompanying CRFs guide the capture of additional desired 
data from the subject’s medical record. 
Participating Centers and Eligible Population 
 
Three centers will participate in this study. Investigators at Seattle Children’s Hospital (SCH), Stanford 
University Lucille Packard Children’s Hospital (LPCH) and Los Angeles Children’s Hospital (LACH) will 
participate.    Seattle Children’s has recently had a personnel change with exit of a surgeon.  Surgical volume 
has increased and complexity remains at high level since that surgeon’s departure.   All three principal 
investigators (M Portman, R. Mainwaring, L. Hastings), at the individual sites participated as site PI for the 
original TRICC trial, although Stanford will be a new site for this study.  Dr. Steve Roth, Co-PI performed a 
single center clinical trial using Triostat at Boston Children’s, and has relocated to Stanford.  Therefore, all the 
investigators are extremely experienced in conducting clinical trials in this population, and all have previously 
used this drug in clinical trials. The three centers are the major tertiary centers for Pediatric Cardiac surgery for 
the entire U.S. West coast.  Together these centers provide a potential surgical volume of near 400 patients 
per year within the age group for recruitment.  Enrollment rate for the TRICC trial was near 70% of patients 
approached.  Therefore, we are optimistic that we can complete enrollment within the time frame of the grant 
(4 years).    
                  
Table 2. Summary of Potential Eligible Patients per Year 
 
 
Blinding and Randomization 
All treating physicians will be blinded to study treatment. All intensive care treating physicians will agree to 
terminate mechanical ventilation based on patient related parameters and to minimize non-patient related 
delays. Clinical practice regarding use of inotropic agents will not be specified in the protocol and will be left to 
standard of care at each participating institution.   Randomization will be performed by site pharmacy staff, who 
will be unblinded. Randomization will be blocked to maintain equal numbers divided between Triostat and 
placebo groups at individual centers, and equal numbers of patients between treatment and placebo for the 
following strata: 
 
1. Less than or equal to 30 days of age 
2. Greater than 30 days of age, less than 152 days of age 
 
SITE
SCH
LPCH
LACH
TOTAL
PI
MP
RM
LH
< 5 MONTHS
93
120
178
391
< 4 weeks
56
81
158
295


Page 18 of 25 
 
Blood samples for Total T3, free T3, and TSH levels (in that order of priority if there are timepoints with 
insufficient volume) will be drawn prior to surgery, just prior to the first infusion and 6 ± 1, 12 ± 1, 24 ± 
1, and 72 ± 1 hours after cross clamp removal or surrogate time point if patient does not undergo 
cross-clamping    Samples for free T3, total T3, and TSH levels will be forwarded to a central laboratory 
(SCH) for processing and analyses. 
 
Data Recording 
All data will be recorded on clinical research forms continuously until the patient is discharged or 30 days, 
whichever is shorter.   Echocardiograms are not required by protocol, but data will be extracted from clinically 
indicated and performed echocardiograms.  
 
Statistical Analysis 
Time to extubation (TTE) for the entire population is the primary clinical endpoint. The target sample size (total 
220 enrolled) was calculated to provide statistical power of >80% to identify a treatment effect on TTE 
corresponding to a hazard ratio of 1.55 with an overall type I error level of 0.05 (2-sided).  Patients will be 
block-randomized into age groups < 4 weeks and > or equal to 4 weeks, with a minimum of 100 patients who 
are ≥ 4 weeks of age. These requirements will provide sufficient numbers for subgroup analyses (see below).  
 
The primary analysis will be performed using Cox Proportional Hazards, including terms for stratification 
factors, and delayed sternal closure.  Patients will be included in analyses if they were randomized and 
received at least one dose of study drug according to the principal of Intention-to-Treat (ITT). Occasionally 
patients are randomized and then surgery is cancelled or rescheduled due to scheduling conflicts, and not due 
to patient related issues.  This can rarely result in the patient missing the study medication when the operation 
is rescheduled at the last minute.  However, since this study is double-blind, the ITT principal is preserved 
because the treatment assignment is blinded and so unknown to persons responsible for these decisions.  
As stated in ICH-E9, Statistical Principles for Clinical Trials posted on the FDA website: “Subjects who fail to 
satisfy an entry criterion may be excluded from the analysis without the possibility of introducing bias only 
under the following circumstances: In some situations, it may be reasonable to eliminate from the set of all 
randomized subjects any subject who took no trial medication. The intention-to-treat principle would be 
preserved despite the exclusion of these patients provided, for example, that the decision of whether or not to 
begin treatment could not be influenced by knowledge of the assigned treatment.” 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073137.pdf 
 
 Thus, patients randomized but not receiving study medication will not be included in the analysis.  
Counting patients who receive at least 1 dose of study drug will improve the scientific validity of the study, and 
reduce the overall cost and duration of this trial. Patients who receive at least 1 dose will be analyzed 
according to randomization assignment regardless of the treatment actually received. The TTE distributions will 
be compared across treatment groups using the Log-Rank test. Time zero will be defined as the time of cross-
clamp removal, and span until to the first of death, extubation or 21 days. Patients who die will be censored at 
the earliest of 21 days or death, and patients who are still intubated at 21 days post-cross clamp removal will 
be censored at 21 days. Medians and 95% confidence intervals for TTE will be based on the Kaplan-Meier 
estimate to account for censoring. A sensitivity analysis adjusting for non-patient-related delays will also 
be performed to determine the impact of these delays, which we expect to be few, on the primary 
efficacy analysis. Differences in death will be compared using Fisher’s Exact Test.   
Secondary endpoints as previously described will be analyzed using similar methodology. Endpoints 
with censored observations will be addressed using survival analysis techniques to account for censoring. 
 


Page 19 of 25 
 
This study is powered to detect a hazard ratio of 1.8 with respect to TTE in patients less than 4 weeks 
of age (assuming half of the total sample is in this age range). The effect in patients < 4 weeks of age is an 
important clinical outcome as these are the sickest patients in the population, and reduction in their relatively 
long intubation times provides more opportunity for benefit.  There will be no Type I error adjustment for this 
subgroup analysis in order to maximize power for the primary outcome, but the sample size was determined 
considering the need to report the effect in the youngest patients. Thus, this analysis will be considered 
supportive and will be described as such in subsequent publications. 
Patient characteristics and adverse events will be compared using the chi-square test or Fisher’s Exact 
test as appropriate. Continuous characteristics and outcomes will be compared using the T-test or ANOVA for 
repeated measures. Point estimates for hazard ratios and 95% (2-sided) confidence intervals will be reported.  
Safety endpoints include arrhythmias, infection rate, serious, and non-serious adverse events. Only 
treatment-emergent events with signs or symptoms that begin or worsen after the first dose of study drug will 
be reported.    
 
Total T3 levels will be analyzed to determine half-time using a single compartmental pharmacokinetic 
model similar to previously published methodology by the PI 29.  
 
Safety 
Adverse Event (AE) Reporting 
Reporting of adverse events in cardiac surgical trials in infants is complicated as there is no regulatory 
guidance specific to conducting clinical research in critically ill children.  The Pediatric Heart Network reported 
a new method of reporting using predefined “sentinel events” in place of serious adverse events (SAEs).  All 
other adverse events were reported as “complications”.  The standard definitions using “Common Terminology 
Criteria for Adverse Events” (CTCAE), developed by the National Cancer Institute does not carry enough 
appropriate pediatric codes to cover the complexity of the postsurgical population.  The Pediatric Heart 
Network (PHN) launched the Single Ventricle Reconstruction Trial and midway switched from standard 
reporting to their new system identifying “sentinel events”30, 31.   This system reduced administrative burden 
and improved quality of safety reporting.  However, their study which evaluated surgical techniques against 
one another was not performed under IND and according to PHN investigators their system has not been 
reviewed by the FDA.    On query regarding the appropriateness for using the PHN published method for 
reporting adverse events in a drug trial the FDA responded: “Our goal is to understand the effect of said study 
treatment on adverse events, i.e., "adverse reactions" (to study drug), not to catalog all bad things that happen 
to subjects. In this respect, the process PHN followed may or may not be reasonable. One would need to think 
through whether the experimental treatment had any likelihood of affecting the common adverse events 
associated with surgery and whether the investigators were likely to be able to distinguish study treatment-
related events from "normal" (clinically expected) ones. “   
 
As TRICC-2 will be performed with IND requirements, we will need to report adverse events (AEs) using FDA 
standards revised by the common rule amendments of 21 CFR Parts 312 and 320 (April 2011).   The common 
rule does reduce reporting requirements somewhat as long as expected AEs and SAEs are predefined in the 
study protocol (see Appendix 1).   A summary of adverse events reported for the TRICC trial appears in Table 
3.   This shows that the majority of patients show AEs, though relatively few have SAEs using standard 
reporting methodology.  Thus, the greatest burden for reporting may not be related to SAEs but to reporting of 
common procedural complications as AEs regardless of severity.  Using literature review and expert 
consensus, the PHN developed lists defining common and specific AEs which occur in this infant population 
undergoing cardiac surgery.  Protection of Human Subjects (section 6) contains a list adapted from the PHN, 


Page 20 of 25 
 
which defines expected surgical complications or AEs.   For instance pleural effusion is defined as an adverse 
event when drainage exceeds 7 days after surgery.   This definition will reduce reporting of pleural effusions.   
In an effort to address the issue raised by the FDA with regard to affect on common adverse events in this 
population, we have numerically coded the complication table generated by the PHN (section 6).  
 
Placebo 
Total
Triostat 
Total
Placebo, < 
5 months
Triostat, < 
5 months
(N=95)
(N=98)
(N=50)
(N=48)
At Least One AE
82 (86.3%)
80 (81.6%)
0.376
45 (90.0%)
42 (87.5%)
0.695
At Least One 
Serious AE
12 (12.6%)
14 (14.3%)
0.736
8 (16.0%)
8 (16.7%)
0.929
At Least One 
Unexpected AE
40 (42.1%)
40 (40.8%)
0.856
25 (50.0%)
22 ( 45.8%)
0.68
At Least One 
Possibly 
Treatment-
Related AE
45 (47.4%)
57 (58.2%)
0.151
26 (52.0%)
34 (70.8%)
0.065
Death (any time 
on study)
5 (5.3%)
3 (3.1%)
0.493
4 (8.0%)
3 (6.3%)
1
Death or 
Mechanical Life 
Support
5 (5.3%)
3 ( 3.1%)
0.493
4 ( 8.0%)
3 ( 6.3%)
1
Arrhythmia AE
9 (9.5%)
11 (11.2%)
0.69
7 (14.0%)
7 (14.6%)
0.934
JET
7 (7.4%)
8 (8.2%)
0.837
5 ( 10.0%)
5 (10.4%)
0.946
SVT
2 ( 2.1%)
3 ( 3.1%)
1
2 (4.0%)
2 (  4.2%)
1
VT
1 ( 1.1%)
0 ( 0.0%)
0.492
1 ( 2.0%)
0 ( 0.0%)
1
 Summary of Adverse Events from Time of Surgery to the First of Hospital Discharge, 
30 Days Post-procedure or Death for entire cohort and < 5 months
P 
P
 
 
Compliance and Monitoring 
IND # 55367 has been assigned by the FDA, which has instructed the PI that amendment and modification 
only is needed for performance of TRICC-2, rather than new IND.  IND amendment was submitted on 
December 8.  We will subcontract with an independent clinical research organization (CRO) to perform 
monitoring for our study.   The CRO, Clinical Research Staff Support Core (CRSSC), has considerable 
experience in monitoring the conduct of clinical trials in children.  The TRICC-2 study will be performed under 
the Guidelines of Good Clinical Practices as outlined in FDA document “Guidance for Industry E6 Good 
Clinical Practice: Consolidated Guidance”.   
 
We will list the study on ClinicalTrials.gov.  Dr. Portman as PI and holder of the IND will serve as sponsor.  
Division of responsibilities between the PI and the CRO are included in the table below.  The PI will be 
supported by experienced study personnel at the Seattle Site.  X = responsible; NR –not responsible, SIV – 
site initiation visit, IMV, interim monitoring visit, COV- close out visit.  
 
Table 3.  TRICC data. Table shows 
no significant difference in rates of 
adverse events between placebo 
and Triostat groups.  Postoperative 
arrhythmias served as an index 
safety factor.   


Page 21 of 25 
 
Table 4.  Division of Interim Monitoring Duties between Sponsor (M. Portman) and Clinical Research 
Organization (CRSSC).  
 
PI
CRO
X
NR
NR
X
NR
X
NR
X
NR
X
NR
X
NR
X
NR
X
NR
X
X
NR
NR
X
NR
X
X
NR
X
NR
x
NR
4.  Final review and approval of monitoring reports
4.  Submit essential documents to regulatory agency
Monitoring
1.  Collect required essential documents including CRFs from each site
2.  Provide Monitoring services (SIV, IMV, COV) at  US sites; 200 patients; First IMV 
after enrollment of 2 patients; subsequent visits after enrollment of 5 patients at each 
site.
1.  Qualify sites
3.  Provide monitoring reports and follow up letters to sites after each visit
3.  Provide essential regulatory documents (e.g. CV of PI, FDA1572 Form, IRB 
approval) to Dr. Portman for submission to regulatory agency (FDA)
Regulatory
2.  Review and approve essential documents
9.  Track IND safety reports
5.  Conduct drug accountability at site during IMVs  (see below)
6.  Review SAEs during IMVs
5.  Track regulatory documents for all sites
6.  Assist sites with regulatory submission to IRBs
7.  Submit SAEs to regulatory agency
8.  Prepare IND safety reports for submission to sites, DMC, and regulatory agency
 
Monitors will be blinded.  Therefore, they cannot perform on-site drug accountability monitoring.  This task will 
be performed by the Seattle Children’s Investigational Drug Service pharmacist for all sites.  
Data Management 
Seattle Children’s Hospital and Research Institute will serve as the central site and data repository.  The CRO 
will oversee completion of clinical research forms (CRFs) and transfer original CRFs to SCH for input into the 
central data base.  Dr. Portman’s staff will generate final queries to each site.   The Research Electronic Data 
Capture (REDCap) database created at Vanderbilt University will be used as the study database.   We will use 
a double entry to avoid input errors.   Data will be stripped of identifiers (according to HIPAA) prior to transfer. 
Each patient will be assigned a study number with code to identifiers kept securely at each individual site.   The 
database will undergo intermittent internal audit to ascertain that CRF data are correctly inputted.  The auditor, 
not yet assigned, will be a different individual than Database manager.  
 
Data Monitoring Committee 
The DMC will be an independent multidisciplinary group consisting of clinicians with collective experience in 
the management of infants after cardiopulmonary bypass and in the conduct and monitoring of clinical trials.  
DMC members will be pediatric cardiologists, pediatric cardiac surgeons and/or pediatric cardiac intensivists, 
and a bioethicist. A biostatistician will also serve on the DMC to advise the committee on the interpretation of 
statistical data provided by the independent statistician.  Members will be appointed by the DMC Chair in 
consultation with Dr. Portman. Blinded and unblinded data reports will be produced by an independent 
statistician at Axio Research. This statistician will be available to present unblinded analyses in the closed 
sessions of the DMC meeting. The DMC will ratify a charter at their first meeting.  
 
 
 


Page 22 of 25 
 
Appendix 1: Listing of Expected AE’s 
 
1. Cardiac General 
1.1 Arrhythmia (recorded if requires medication or treatment) 
1.1.1 Atrial fibrillation 
1.1.2 Atrial flutter 
1.1.3 Supraventricular tachycardia 
1.1.4 Junctional ectopic tachycardia 
1.1.5 Sinus node dysfunction (requiring pacing) 
1.1.6 Atrioventricular block(second or third degree) 
1.1.7 Ventricular tachycardia 
1.1.8 Ventricular fibrillation 
1.2 Mediastinum 
1.2.1 Hemopericardium (requiring intervention, includes postoperative mediastinal hemorrhage) 
1.2.2 Pericardial effusion (requiring drainage) 
1.2.3 Postpericardiotomy syndrome (requiring treatment) 
1.3 Cardiac performance 
1.3.1 Hypotension (<40 mm Hg for neonates; <50mm Hg after stage II surgery) 
1.3.2 Hypertension (requiring long-term therapy, ie, >30 days after discharge, therapy should be 
at the therapeutic doses and specifically prescribed for the treatment of hypertension) 
1.3.3 RV dysfunction(requiring  escalation or initiation of therapy, not to include immediate 
postoperative dysfunction routinely associated with cardiopulmonary bypass) 
1.3.4 Semilunar valve insufficiency or stenosis (requiring treatment initiation or escalation) 
1.3.5 Atrioventriuclar valve insufficiency or stenosis (requiring treatment initiation or escalation) 
1.3.6 Prosthetic valve dysfunction 
1.4 Great vessels 
1.4.1 Superior vena cava stenosis (anatomic, symptomatic, “superior vena cava syndrome”) 
1.4.2 Superior vena cava occlusion 
1.4.3 Inferior vena cava occlusion 
1.4.4 Other cardiovascular 
2.  Respiratory 
2.1 Chronic respiratory failure (intubated for >2 weeks after surgery) 
2.2 Chylothorax (postoperative accumulation of chylous fluid in the pleural space requiring intervention 
whether by evacuation, dietary change, and /or medical treatment) 
2.3 Hemothorax (requiring drainage) 
2.4 Phrenic nerve injury/diaphragmatic paralysis (newly elevated diaphragm on chest x-ray film) 
2.5 Pleural effusion (requiring drainage >7 days after surgery, other) 
2.6 Pneumothorax (requiring tube insertion) 
2.7 Tracheal injury 
2.8 Vocal cord injury (direct  visualization) 
2.9 Airway obstruction (requiring a significant intervention) 
2.10 
Hypoxia (requiring readmission or escalation of care) 
2.11 
Other respiratory 
3.  Neurologic 
3.1 Choreoathetosis/posturing (moderate involuntary movements interfering with function) 
3.2 Coma 


Page 23 of 25 
 
3.3 Intracranial bleeding (confirmed by imaging) 
3.4 Seizure(s) (confirmed by electroencephalogram or obvious motor signs) 
3.5 Stroke (confirmed by imaging study) 
3.6 Hydrocephalus (report if CTCAE grade >2) 
3.7 Neurologic deficit persisting at discharge not attributed to any of the above diagnoses 
3.8 Other neurologic 
4.  Gastrointestinal 
4.1 Direct bilirubin >4 umol/L 
4.2 Liver failure (AST, ALT, or GGT > 500 U/L) 
4.3 Necrotizing enterocolitis, confirmed (pneumatosis or free air) 
4.4 Necrotizing enterocolitis, suspected (NPO, antibiotics started) 
4.5 Other esophageal or bowel perforations not associated with necrotizing enterocolitis 
4.6 Upper gastrointestinal bleed, requiring treatment 
4.7 Stricture/stenosis (CTCAE > grade 2) 
4.8 Other  gastrointestinal 
5.  Infectious 
5.1 Empyema 
5.2 Endocarditis 
5.3 Gastroenteritis  or enteritis 
5.4 Line infection, bacterial ( positive blood cultures) 
5.5 Line infection, fungal ( positive blood cultures with initiation of therapy) 
5.6 Pneumonia, respiratory infection, viral (requiring the initiation of therapy) 
5.7 Mediastinitis/wound infection, deep (requiring incision and drainage; sternal instability) 
5.8 Wound infection, superficial (erythema, possible tissue separation and drainage) 
5.9 Sepsis, confirmed (positive blood cultures, not line infection) 
5.10 
Sepsis, clinical with negative cultures 
5.11 
Urinary tract infection 
5.12 
Other infection 
6. Renal 
6.1 Acute renal failure (creatinine> 1.5mg/dL (133umol/L) or tripling of baseline value for <7 days; 
temporary dialysis) 
6.2 Chronic renal failure (creatinine >1.5mg/dL (133 umol/L) or tripling of baseline value for >7 days; 
long-term dialysis) 
6.3 Other renal  
6.4  Hematologic Anemia (hemoglobin <10 gm/L) 
6.5 Thrombocytopenia (platelets < 50 x 10(9)/L) 
6.6 Hematoma (CTCAE grade > 2) 
6.7 Hemorrhage, gastrointestinal (CTACE grade >2; hemepositive stools) 
6.8 Hemorrhage, genitourinary (CTCAE grade > 2) 
6.9 Hemorrhage, pulmonary/upper respiratory (CTCAE grade > 2) 
6.10 
Other hematologic 
7. Vacular 
7.1 Thrombus/thromboembolism 
7.2 Vascular, other 
8.  Other complication 
9.1 Other 


Page 24 of 25 
 
RV, Right Ventricular; CTCAE, Common Terminology Criteria for Adverse Events; AST, aspartate 
aminotransferase; ALT, alanine aminotransferase; GGT, gamma-glutamyl transferase; NPO, nothing by mouth. 
 
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