Colchicine in Postoperative Fontan Patients (CPFP)
Phase: PHASE2
Conditions: Single-ventricle, Heart Diseases
Sponsor: University of Michigan

NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
Colchicine in Postoperative Fontan Patients (CPFP)– v1.0 v 
 
Colchicine in Postoperative Fontan Patients (CPFP) 
Protocol Number: 1 
National Clinical Trial (NCT) Identified Number:  NCT03575572 
Principal Investigators: Albert Rocchini, MD, Stephanie Goldstein, MD 
Funded by: University of Michigan 
Version Number:  1.5 
06 March 2020 

Colchicine in Postoperative Fontan Patients (CPFP) 
Protocol Number: 1 
National Clinical Trial (NCT) Identified Number:  NCT03575572 
Principal Investigators: Albert Rocchini, MD, Stephanie Goldstein, MD 
Funded by: University of Michigan 
Version Number:  1.5 
06 March 2020 
Summary of Changes from Version 1.4 to 1.5: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
4.1, 9.4.6 
Addition of interim analysis 
Due to slower than anticipated recruitment, 
the study team has decided to perform an 
interim analysis.  
8.3.3.3, 8.3.5 
 
Spacing out the frequency of Safety Monitoring 
Committee meetings if there are less than 5 
new patients enrolled 
Since Fontan operations are often seasonal, 
there can be stretches of 6-8 months where 
there are 0-2 new patients enrolled. This 
modification allows for the SMC to postpone 
their next review to the next scheduled time 
if there are less than 5 new patients 
enrolled. 
 
Summary of Changes from Version 1.3 to 1.4: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
4.2, 5.1, 9.3 
Lowering the lower age limit of included 
patients from 24 months to 20 months 
Fontan operations are occurring slightly 
earlier than 24 months. There is no 
difference in risk profile or mechanism of 
action with the administration of colchicine 
to a slightly younger age, as it has been 
studied to be safe and effective in children 
as young as less than one year of age1,2. This 

NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
Colchicine in Postoperative Fontan Patients (CPFP)– v1.0 v 
age change, however, significantly increases 
the patient population who will qualify for 
screening in for this study.  
5.1, 6.1.2, 7.1 
Alteration of the definition of “blood dyscrasia” 
or “myelosuppression” 
After review of literature and discussion 
with Dr. Rajen Mody a clinical trialist in 
Pediatric Oncology, the definition of 
myelosuppresion and blood dyscrasia was 
altered to be: total WBC < 4.0, ANC < 0.1, 
ALC < 0.1, or platelets < 10. Many Fontan 
patients have lower WBC and ALC numbers 
at baseline3 without an increase in infection 
risk4. Altering this criteria allows for 
increased eligible patients without putting 
patients at any increased risk of adverse 
events. 
5.5 
Update to compensation for patients and 
families 
The compensation of a small toy for patients 
and a $25 gift card was already in process 
and part of the informed consent. This 
mistake was recognized upon this 
amendment and therefore updated. 
 
Summary of Changes from Version 1.2 to 1.3: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
4.3, 6.1.2, 7.1, 
8.2 
Altering the wording regarding discontinuation 
of the study intervention secondary to GI 
distress, nausea and vomiting. 
Most postoperative Fontan patients have 
some degree of nausea and vomiting. Upon 
review of the historical cohort that was not 
treated with the study intervention, 8 out of 
12 had at 1-3 days of nausea and vomiting 1-
4 times per day. Due to this, we are 
requesting an alteration of the study 
intervention discontinuation wording to 
include “above expected degree.” 
7.1, 8.2 
Adding a clause that states we can continue or 
restart  the study intervention if a noted 
adverse event is not related or unlikely to be 
related to the intervention. 
Patients who have an event that is not 
related or unlikely to be related to the study 
intervention are being withdrawn from the 
study, despite the adverse event being 

NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
Colchicine in Postoperative Fontan Patients (CPFP)– v1.0 v 
unrelated to the study intervention based on 
the wording of the protocol.  
8.2 
Addition of “within” to the sentence: follow up 
labs “will be obtained within 1 week following 
discontinuation to ensure resolution” 
If the clinical team obtains repeat labs 
earlier than 1 week that prove resolution of 
the adverse event, repeated studies are not 
necessary.  
1.3, 8.3.4 
Added a range of days for phone call follow up 
It is sometimes not possible to reach families 
on particular days. This allows a range of 
time to reach the family in follow up. 
 
Summary of Changes from Version 1.1 to 1.2: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
5.2 
Addition of exclusion criteria. 
Based on recommendations from IRBMED 
 
Summary of Changes from Version 1.0 to 1.1: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
1.2, 1.3, 5.5, 
8.2 
Addition of call to family prior to informed 
consent as screening for potential interest. 
This was recommended as a first step to 
gauge interest in families, rather than 
approach them without time to think about 
their potential involvement. 
6.1.2, 7.1 
Alter the definition of concerning dyscrasia 
related to the study intervention. 
Patients may have altered CBCs after 
surgery that is not related to the study 
intervention. Therefore, we altered the 
definition to account for this. 
6.2.2, 6.3.3 
Update the information about the colchicine 
information currently used at Michigan 
medicine 
This was a recommendation from the IDS 
subcommittee based on the current 
hospital formulary. It was taken from the 
new colchicine package insert. 

NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
Colchicine in Postoperative Fontan Patients (CPFP)– v1.0 v 
1.1, 1.2, 1.3, 
3, 8.1, 9.1, 
9.2, 9.4.2, 
Delete the blood cytokine portion of the 
protocol. 
Upon scientific review during grant 
proposal, this was thought to be 
unnecessary for the purposes of our 
hypothesis. It was not funded, and we have 
removed it from our protocol.  
10.1.5 
Updated contact information 
The email that was listed was the non-
institutional email for the Co-PI 

  
Colchicine in Postoperative Fontan Patients (CPFP)– v1.0 v 
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 2 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 5 
2 
INTRODUCTION ............................................................................................................................................ 5 
2.1 
Study Rationale .................................................................................................................................... 5 
2.2 
Background........................................................................................................................................... 6 
2.3 
Risk/Benefit Assessment .................................................................................................................... 7 
2.3.1 
Known Potential Risks ..................................................................................................... 7 
2.3.2 
Known Potential Benefits ................................................................................................ 8 
2.3.3 
Assessment of Potential Risks and Benefits ................................................................ 8 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 9 
4 
STUDY DESIGN ........................................................................................................................................... 10 
4.1 
Overall Design .................................................................................................................................... 10 
4.2 
Scientific Rationale for Study Design.............................................................................................. 11 
4.3 
Justification for Dose ......................................................................................................................... 11 
4.4 
End of Study Definition ..................................................................................................................... 11 
5 
STUDY POPULATION ................................................................................................................................ 11 
5.1 
Inclusion Criteria ................................................................................................................................ 11 
5.2 
Exclusion Criteria ............................................................................................................................... 11 
5.3 
Lifestyle Considerations .................................................................................................................... 12 
5.4 
Screen Failures .................................................................................................................................. 12 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 12 
6 
STUDY INTERVENTION ............................................................................................................................ 13 
6.1 
Study Intervention(s) Administration ............................................................................................... 13 
6.1.1 
Study Intervention Description ..................................................................................... 13 
6.1.2 
Dosing and Administration ............................................................................................ 13 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 14 
6.2.1 
Acquisition and accountability ...................................................................................... 14 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 14 
6.2.3 
Product Storage and Stability ....................................................................................... 15 
6.2.4 
Preparation ...................................................................................................................... 15 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 15 
6.4 
Study Intervention Compliance ........................................................................................................ 15 
6.5 
Concomitant Therapy ........................................................................................................................ 15 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 16 
7.1 
Discontinuation of Study Intervention ............................................................................................. 16 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 17 
7.3 
Lost to Follow-Up ............................................................................................................................... 17 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 17 
8.1 
Efficacy Assessments ....................................................................................................................... 17 
8.2 
Safety and Other Assessments ....................................................................................................... 20 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 21 
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 21 

  
Colchicine in Postoperative Fontan Patients (CPFP)– v1.0 v 
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 21 
8.3.3 
Classification of an Adverse Event .............................................................................. 21 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 23 
8.3.5 
Adverse Event Reporting .............................................................................................. 23 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 23 
8.3.7 
Reporting Events to Participants ................................................................................. 24 
8.4 
Unanticipated Problems .................................................................................................................... 24 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 24 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 24 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 25 
9.1 
Statistical Hypotheses ....................................................................................................................... 25 
9.2 
Sample Size Determination .............................................................................................................. 26 
9.3 
Populations for Analyses .................................................................................................................. 26 
9.4 
Statistical Analyses............................................................................................................................ 26 
9.4.1 
General Approach .......................................................................................................... 27 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 27 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 27 
9.4.4 
Safety Analyses .............................................................................................................. 28 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 28 
9.4.6 
Planned Interim Analyses ............................................................................................. 28 
9.4.7 
Sub-Group Analyses ..................................................................................................... 28 
9.4.8 
Tabulation of Individual participant Data .................................................................... 28 
9.4.9 
Exploratory Analyses ..................................................................................................... 28 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 28 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 28 
10.1.1 
Informed Consent Process ........................................................................................... 28 
10.1.2 
Study Discontinuation and Closure ............................................................................. 29 
10.1.3 
Confidentiality and Privacy ........................................................................................... 30 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 30 
10.1.5 
Key Roles and Study Governance .............................................................................. 31 
10.1.6 
Safety Oversight ............................................................................................................. 31 
10.1.7 
Clinical Monitoring .......................................................................................................... 31 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 31 
10.1.9 
Data Handling and Record Keeping ............................................................................ 32 
10.1.10 
Protocol Deviations ........................................................................................................ 33 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 33 
10.1.12 
Conflict of Interest Policy .............................................................................................. 33 
10.2 
Additional Considerations ................................................................................................................. 34 
10.3 
Abbreviations ...................................................................................................................................... 35 
10.4 
Protocol Amendment History ........................................................................................................... 37 
11 
REFERENCES ............................................................................................................................................. 39 
 

CPFP 
Version 1.1 
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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.] 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
The effect of empiric Colchicine on inflammatory cytokines in 
postoperative Fontan pleural drainage 
Study Description: 
Prolonged pleural drainage is a common complication of postoperative 
Fontan patients. There is elevation of inflammatory cytokines in the 
Fontan population out of proportion to age-matched controls, with 
increase over time. Colchicine is an anti-inflammatory agent with a low 
side-effect profile that may target the pro-inflammatory cytokines seen 
elevated in post-operative Fontan patients. The hypothesis of this study is 
that empiric Colchicine will decrease pro-inflammatory cytokines and 
therefore may decrease the duration of pleural drainage in post-operative 
Fontan patients.  
Objectives: 
 
 
Primary Objective:  Determine if Colchicine is associated with decreased 
inflammatory cytokines (TNF-α) within the pleural space in post-operative 
Fontan patients compared to a historical cohort of Fontan patients  
Secondary Objective:  
1. Examine the cytokine concentrations in Fontan patients treated 
empirically with Colchicine in comparison to a cohort of Fontan 
patients at a given time-point postoperatively. 

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2. Determine if Colchicine is associated with decreased duration of 
pleural drainage in post-operative Fontan patients compared to a 
cohort of Fontan patients  
3. Determine if Colchicine reduces hospital length of stay following 
Fontan procedure 
 
 
 
Endpoints: 
Primary Endpoint: Change in Cytokine concentrations (TNF-α) from 
postoperative day 1 (POD1) to the day most distal from surgery (DMD) in 
pleural fluid in patients s/p Fontan palliation treated with Colchicine  
Secondary Endpoints:  
1. Cytokine concentrations (particularly TNF-α, MIP-1βm, IL-17A, IL-8, 
and INF-γ) in Fontan patients treated with Colchicine at a given 
time-point postoperatively 
2. Duration of pleural drainage in Fontan patients treated with 
Colchicine. 
3. Hospital length of stay in Fontan patients treated with Colchicine 
Study Population: 
25 patients undergoing Fontan operation ages 24 months to 5 years and 
364 days at the University of Michigan Congenital Heart Center. 
  
Phase: 
2 
Description of 
Sites/Facilities Enrolling 
Participants: 
The study will be performed at one site: The University of Michigan  
 
Description of Study 
Intervention: 
 
Colchicine, an anti-inflammatory drug will be given on postoperative day 2. 
Colchicine will be given at 0.6 mg once daily for the duration of chest tube 
output plus 24 hours after chest tube removal with a maximum of 4 weeks 
duration.  
Study Duration: 
24 months 
Participant Duration: 
10 days, on average based on median hospitalization in control cohort. 
 
 
1.2 
SCHEMA 
 
 
 
Example #1 Flow diagram (e.g., randomized controlled trial) 

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Prior to  
Enrollment 
 
 
Visit 1Pre- 
Operative  
Day 
 
Visit 2  
Operative  
day 
 
 
 
Visit 3 
Hospitalization 
Day 1 to Y  
 
 
 
 
Hospitalization  
Day 2 to Y +  
24 hours 
 
 
Hospitalization 
Day 2 to Y +  
24 hours 
 
 
 
 
 
 
 
Post Sample  
collection 
 
 
 
Screen potential participants by inclusion and exclusion criteria 
Collect pleural drainage samples* on post-
operative days (POD) 1,2,3,4,7,10,14, 21, and 28 or 
until chest tubes are discontinued. Samples are 
frozen 
*Additional sample may be collected on first day of 
diagnosis of “chylous” fluid, if collection not 
otherwise planned 
Follow-up assessments of safety on POD 3,4,7,14, 21 and 28 or until chest tube is removed 
during drug delivery. Survey of GI discomfort and infections daily. CBC and comprehensive 
metabolic panel will be obtained on POD 4, 7, and weekly thereafter during drug delivery 
Pleural samples analyzed together as 
a batch 
 
Give Colchicine (study drug) once daily 
 Call families of potential participants to discuss trial 
Collect medical record 
information 
Y= chest tube removal date or a second chest intervention 
Total N-25:Obtain Informed consent 

CPFP 
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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures 
Screening 
Day -30 to -1 
Enrollment/Baseline 
Visit 1: Hospitalization, 
POD 1a  
Hospitalization, POD 2 
Hospitalization, POD 3 
Hospitalization, POD 4 
Hospitalization, POD 5 
Hospitalization, POD b 
Hospitalization, POD 7 
Hospitalization, POD 
10 
Hospitalization, POD 
14 
Hospitalization, POD 
21 
Hospitalization, POD 
28 
 Hospitalization, POD Z 
 Phone call, c+5-14 
days 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Operation* 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pleural fluid collection 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
 
Review and record relevant 
medical history and 
medication history  
x 
-----------------------------------------------------------------------------------------------------------  x 
 
Drug delivery once dailyc 
 
 
x -----------------------------------------------------------------------------------------  x 
 
 
 
CBC, Renal function panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC, comprehensive 
metabolic panel 
 
 
 
 
X 
 
 
x 
 
x 
x 
x 
 
 
Complete Case Report Forms 
(CRFs) with AE recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
a:       POD is defined as midnight to midnight (calendar day). 
b:       This collection will only be obtained on the first day of the diagnosis of “chylous” fluid  
c:       Drug delivery continues for duration of chest tube drainage or re-intervention in the chest + 24 hours for a maximum duration of 4 
weeks 
Z: 
Hospital discharge 
*: operation is per clinical care; not part of the study 
 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
Prolonged pleural drainage and chylothorax are common complications post Fontan procedure 
and are associated with short and long term morbidities such as prolonged hospital stay, protein losing 
enteropathy, and plastic bronchitis. Our previous study showed a statistically significant increase in pro-
inflammatory cytokines (specifically IL 8, IL-17A, INF-ɣ, TNF-α, MIP-1β) localized to the pleural space in 
comparison to age-matched controls. Our study also showed a longer duration of pleural drainage and 
thus longer hospitalization in the Fontan study group. While prolonged pleural drainage in this 
population is likely multifactorial, with suspected etiologies including thoracic duct injury, and increased 
lymphatic pressures, our hypothesis is that localized inflammation contributes to this prolonged pleural 
drainage. Colchicine is an anti-inflammatory medication that has been used in pericarditis, persistent 
pericardial effusions, Familial Mediterranean Fever, and Gout and many other inflammatory diseases, 
and has mechanisms of action that target TNF-α and INF-ɣ, among other inflammatory cytokines. We 
hypothesize that addition of colchicine to empiric treatment of post-operative Fontan patients will 

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decrease inflammatory cytokines within the pleural space and therefore may decrease the duration of 
pleural drainage, thus shortening hospitalization and potential hospital-associated complications. 
 
2.2 
BACKGROUND  
 The Fontan procedure, introduced in 1971, is the final of three stages of palliation for patients 
born with single ventricle heart disease and involves creation of a total cavo-pulmonary connection 
typically performed at 2-3 years of age.5  This procedure has enabled many children born with previously 
fatal defects to live into adulthood. With advancements in surgical techniques and perioperative 
management, morbidity and mortality from Fontan palliation has improved but remain significant.6 One 
challenging problem in the immediate postoperative care of the Fontan patient is prolonged pleural 
drainage. The rate of pleural effusions in patients with functional single ventricles ranges from 12% to 
45%7, and remains a dominant morbidity associated with increased postoperative length-of-stay. It has 
also been associated with an increased risk of protein losing enteropathy and plastic bronchitis and 
diminished short- and long-term survival.8–10 Currently, treatment methods include Fontan fenestration, 
aggressive diuresis, low fat diet, parenteral nutrition, and time.11  Octreotide administration, thoracic 
duct ligation, and pleurodesis are reserved for refractory drainage with variable results.12  Rare 
alternative treatment methods have been attempted to no avail including diaphragmatic fenestration13 
and angiotensin-converting enzyme inhibitor use,14 however, no treatment methods have ideal results 
and patients requiring treatment often continue to drain. 
The etiology for prolonged pleural drainage in a Fontan patient is likely multifactorial. Fontan 
patients have hemodynamic characteristics that favor pleural fluid accumulation including elevated 
central venous pressures, elevated right ventricle (RV) end-diastolic pressure from poor ventricular 
compliance or neo-aortic valve regurgitation, elevated pulmonary vascular resistance, or significant 
aortopulmonary collaterals. The inadvertent surgical disruption of lymphatic channels during the Fontan 
surgery may cause extravasation of chylous fluid and compromise local lymphatic function. Activation of 
the inflammatory and complement cascades during the course of cardiopulmonary bypass (CPB) can 
cause vascular capillary leak to promote the development of effusions.7  Patients undergoing the Fontan 
procedure have been shown to have significantly increased postoperative plasma levels of inflammatory 
cytokine and complement production compared to preoperative levels.15  Also, cytokine and 
complement levels were significantly higher in patients who had the Fontan procedure with CPB 
compared to patients who had the Fontan procedure off pump.16  
 A recent study from our institution showed a significant increase in pro-inflammatory cytokines 
(IL-17A, IFN-γ, MIP-1β, and TNF-α) localized to the pleural space in the postoperative Fontan population 
in comparison to age-matched controls undergoing CPB. Inflammatory cytokines ((IL-8, MIP-1β, and 
TNF-α) increased over time in the Fontan population, while an anti-inflammatory cytokine, IL-10, 
decreased over time. The control population had no such changes. TNF-α in particular was significantly 
elevated in Fontan patients as compared to controls on DMD from surgery, it had a significant increase 
over time in the Fontan group, whereas the control group had no such change. The change over time in 
comparison to the control group was also significantly different. 17 This suggests an exaggerated ongoing 
inflammatory response or process in the postoperative Fontan population that is not a result of 
cardiopulmonary bypass alone, particularly in the well described pro-inflammatory cytokine TNF-α. 
Colchicine is a widely used and widely recognized drug and has been used to treat acute and 
recurrent pericarditis18–21, to reduce postoperative pericardial and pleural effusions, shortening 
postoperative hospital stays after cardiac surgeries in adults22,23, and even reduce post-pericardiotomy 

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syndrome24,25. It was also shown to acutely suppress local cardiac production of inflammatory cytokines 
in patients with acute coronary syndrome 26. Colchicine modulates multiple pro-inflammatory pathways. 
It prevents microtubule assembly, thereby disrupting inflammasome activation, microtubule-based 
inflammatory cell chemotaxis, generation of leukotrienes, and cytokines, and phagocytosis. 27 It also 
impairs neutrophil function by impacting inflammatory pathways and mediators of neutrophil 
activation. It is used in multiple inflammatory conditions, including gout, Behҫet’s syndrome, primary 
biliary cirrhosis, alcohol-induced liver cirrhosis, psoriasis, Sweet’s syndrome, scleroderma, sarcoidosis, 
and Familial Mediterranean Fever. 1,28–30 Colchicine blunts TNF-α induced activation of macrophages and 
reduces the number of TNF-α receptors on the surface of macrophages and endothelial cells. 27 It also 
decreases levels of the proinflammatory cytokines IL-1β, INF-ɣ,  IL-18, and IL-6, among others. Our 
previous study demonstrates that, TNF-α and INF-ɣ were shown to be significantly elevated in the 
pleural fluid of postoperative Fontan patients, and increased over time 17. We propose the novel 
hypothesis that Colchicine, given empirically to postoperative Fontan patients, decreases the pro-
inflammatory cytokines within the pleural space and decreases the duration of pleural drainage in post-
operative Fontan patients, thus contributing to shortened hospitalizations. 
While the above studies were all done in adults, Colchicine has been shown to be safe and 
efficacious in children, even as young as less than 1 year of age1,31,32. It is most commonly given in 
children with Familial Mediterranean Fever (FMF), and has minor side-effects 1,2. Typical side effects 
seen are GI distress (diarrhea, cramping) and mildly increased transaminases, but these can be 
controlled by a decrease in the dose.2 Dosage typically given to children for Familial Mediterranean 
Fever ranges from 0.3-2 mg /day in 1-2 divided doses. 1,2,31–38 The FDA approved label dose for children 
ages 4-6 years is 0.3-1.8 mg daily. 
 
Significance 
The etiology of pleural effusions in patients undergoing the Fontan operation is likely multifactorial, and 
many studies indicate that an inflammatory response contributes to this process. Our prior study 
showed a significant elevation in pro-inflammatory cytokines localized to the pleural space in post-
operative Fontan patients as compared to age-matched controls17.  
 
Our study will investigate the novel hypothesis that Colchicine, given empirically, to post-operative 
Fontan patients decreases the pro-inflammatory cytokines within the pleural space and therefore may 
decrease the duration of pleural drainage, thus contributing to shortened hospitalizations. If this is true, 
further studies can be done to extend to multiple centers and to evaluate for potentially decreased long-
term morbidity in post-operative Fontan patients. 
 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
The most commonly reported side effect of Colchicine is GI discomfort, nausea, vomiting, and diarrhea. 
This is a short term risk and has been shown to be mitigated by dose decrease 37. As stated in the FDA 

CPFP 
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8 
 
approved drug label, these effects are usually mild, transient and reversible upon lowering the dose. 
They typically present within 24 hours of initiation of therapy. Survey of symptoms will be performed on 
POD 3 and 4, 24 and 48 hours after initiation of therapy, and POD 7 and weekly thereafter for as long as 
the patient remains on the therapy drug for monitoring. Blood dyscrasias including myelosuppression, 
leukopenia, granulocytopenia, thrombocytopenia, pancytopenia and aplastic anemia have been 
reported with colchicine used in therapeutic doses. A CBC will be collected during blood draws on POD 4 
(2 days after initiation of drug), and POD 7 and weekly thereafter for as long as the patient remains on 
the therapy drug for monitoring. Colchicine-induced neuromuscular toxicity and rhabdomyolysis have 
been reported with chronic treatment. This study period consists of short term treatment, and should 
not be applicable. Colchicine is a P-gp and CYP3A4 substrate, therefore life-threatening and fatal drug 
interactions have been reported in patients treated with colchicine given with P-gp and strong CYP34A 
inhibitors. If a patient is on these classes of drugs, colchicine will not be given. 
 
There is a slight increased risk of infection as part of the collection protocol. The samples are collected in 
a sterile manner from a self-sealing chest tube. This is an immediate risk, and there is no long range risk 
as part of this. As an alternative to needle puncture into the tubing, collections could be obtained via the 
collection box, however this is a collection of multiple days of pleural drainage and is therefore 
inaccurate for the purposes of this study. There is a slightly increased risk of infection secondary to 
blood draws as well, however this is no higher than would be for a clinically indicated blood draw. There 
is a risk of loss of private or confidential information. 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
Colchicine acts as an anti-inflammatory medication. Its primary indication is for gout, an inflammatory 
process. It has also been used in pericarditis, recurrent pericarditis, pericardial and pleural effusions, and 
post-pericardiotomy syndrome in adults with notable improvements in duration of effusions 18–24. It is 
FDA approved for use in young children, primarily for Familial Mediterranean Fever, another 
inflammatory disease. There may be a benefit of decreasing hospital length of stay, as Fontan patient’s 
length of stay is proportional to their duration of chest tube drainage 17. If chest tube duration is 
decreased, this may decrease the risk of long term complications such as protein losing enteropathy and 
plastic bronchitis, as these were associated with chest tube drainage longer than 2 weeks 8,10 
 
There is no specific benefit to the sample collection itself. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
Colchicine is a medication that has been widely used and very well tolerated in pediatric patients. The 
potential for decreased duration of chest tube drainage and decreased hospital length of stay with a 
possible decrease for long term complications associated with Fontan physiology as well, outweighs the 
risk of mild GI discomfort and diarrhea, which is the most commonly reported side effect associated 
with the medication. Additionally, in the studies cited above, if there were complaints of GI discomfort 
or diarrhea, they were ameliorated by a reduction in dose. The warnings of dyscrasias, neuromuscular 
toxicity and rhabdomyolysis are rare and have been reported in cases of overdose or excessive 
accumulation. 
 
Obtaining the samples is necessary to determine if the drug is affecting the proposed mechanism of 
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low, and among the baseline cohort of patient who underwent a similar collection schedule, there were 
no infectious complications.  
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
Determine if Colchicine is 
associated with decreased 
inflammatory cytokines (TNF-α) 
within the pleural space in post-
operative Fontan patients 
compared to a historical cohort of 
Fontan patients  
 
 
Change in Cytokine concentrations 
(TNF-α) from postoperative day 1 
(POD1) to day most distal from 
surgery (DMD) in pleural fluid in 
patients s/p Fontan palliation treated 
with Colchicine  
 
Cytokines correlate with the 
findings from the original study 
on the Fontan cohort. Certain 
cytokines in the Fontan patients 
were elevated (TNF-α, MIP-1β, 
IL-8, IL-17) as compared to age-
matched controls, and increased 
over time, whereas controls did 
not. This endpoint allows us to 
evaluate if colchicine effects 
these changes as the mechanism 
of action if there is decreased 
duration of pleural drainage. 
 
Secondary 
 
 
1. Examine the cytokine 
concentrations in 
postoperative Fontan 
patients treated empirically 
with Colchicine in 
comparison to a cohort of 
postoperative Fontan 
patients at a given time-
point postoperatively 
2. Determine if empiric 
treatment with Colchicine 
is associated with 
decreased duration of 
pleural drainage in post-
operative Fontan patients 
compared to a cohort of 
Fontan patients not treated 
with Colchicine 
3. Determine if empiric 
treatment with Colchicine 
is associated with 
decreased length of stay in 
postoperative Fontan 
patients as compared to a 
1. Cytokine concentrations 
(particularly TNF-α, MIP-1β, 
IL-17A, IL-8, and INF-γ) in 
comparison to postoperative 
Fontan patients at a given 
time-point postoperatively 
2. Duration of pleural drainage 
in Fontan patients treated 
with Colchicine  
3. Hospital length of stay in 
Fontan patients treated with 
Colchicine  
  
1. Cytokines correlate with 
the findings from the 
original study on the 
Fontan cohort. Certain 
cytokines were higher 
(TNF-α, MIP-1β, IL-8, IL-
17) as compared to age-
matched controls, and 
increased over time, 
whereas controls did 
not. This endpoint 
allows us to evaluate if 
colchicine effects these 
changes as the 
mechanism of action if 
there is decreased 
duration of pleural 
drainage 
2. The duration of chest 
tube drainage in 
postoperative Fontan 
patients correlates to 
short and long term 
morbidity.  Our 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
cohort of Fontan patients 
not treated with Colchicine 
 
hypothesis is that 
elevated cytokines 
contribute to longer 
drainage, therefore 
decreasing duration of 
chest tube drainage with 
colchicine treatment is a 
clinically meaningful 
result. 
3. Hospital length of stay 
was proportional to 
chest tube drainage, 
therefore if empiric 
Colchicine is associated 
with decreased chest 
tube drainage, hospital 
length of stay may be 
another clinically 
meaningful result. 
 
 
 
 
 
 
 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
This study’s hypothesis is that certain pro-inflammatory cytokines (TNF-α, MIP-1β, IL-17A, IL-8 and INF-γ) 
are significantly reduced in Fontan patients treated with colchicine as compared to a historical cohort of 
Fontan patients. The secondary hypotheses is that Colchicine, when given empirically to post-operative 
Fontan patients, decreases the median duration of chest tube drainage and hospital length of stay in 
comparison to a cohort of Fontan patients.  
 
This is a phase II trial for efficacy of Colchicine (study intervention) in this population.  
 
The study is a single-arm, single site clinical trial in which all enrolled Fontan patients will be given the 
empiric drug. Selection bias will be minimized as all consenting, eligible Fontan patients will be given the 
empiric drug and this will be in comparison to a historical cohort of Fontan patients who underwent 
surgery all at the same institution where surgical technique is similar. See section 6.1.2 for specific 
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4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The study intervention group will be compared with a historical control group. This control group of 
patients is from the previous study in children ages 20 months to 5 years and 364 days, who underwent 
Fontan palliation at the University of Michigan between April 2016 – October 2016. The study was 
similar, without the study intervention of colchicine administration.  
 
4.3 
JUSTIFICATION FOR DOSE 
In children, Colchicine is most commonly given in children with Familial Mediterranean Fever (FMF), and 
has minor side-effects 1,2. Dosage in clinical use ranges from 0.3-2 mg /day in 1-2 divided doses 1,2,31–38. 
We chose 0.6 mg once daily as the dose based on the largest number of studies with this dosing range to 
maximize effect and minimize side effects. In addition, the drug is formulated in 0.6 mg tablets. There 
will be no titration. If there are complaints of GI distress out of proportion to the expected degree, the 
dose will be decreased to 0.3 mg daily (1/2 tablet). The drug is available in 0.6mg tablets, however 
children within the age-range in this study will not be able to take the medication in this form. The tablet 
will be dissolved in 2-3 mL of either water, juice (non-grapefruit containing) or milk to make a solution 
that is able to be given to children of this age.39,40 This process will be performed per standard hospital 
procedures. The drug may NOT be crushed. The drug may be given via mouth, G-tube, NG tube, or NJ 
tube.  The drug will be prepared beside for immediate use (given within one hour). 
 
 
4.4 
END OF STUDY DEFINITION 
 
The end of the study participation is defined as completion of the last visit shown in the Schedule of 
Activities (SoA) Section 1.3.  
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Provision of signed and dated informed consent form 
2. Parent stated willingness to comply with all study procedures and availability for the duration of 
the study  
3. Male or female, aged 20 months to 5 years and 365 days 
4. Diagnosed with single ventricle heart disease requiring Fontan palliation 
5. Undergoing Fontan palliation at the University of Michigan Congenital Heart Center              
6. Ability to take oral or enteral medication  
 
 
5.2 
EXCLUSION CRITERIA 
 
 An individual who meets any of the following criteria will be excluded from participation in this study: 
 

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1. Current or recent (within 14 days) use of medication with P-gp and strong or moderate CYP34A 
inhibitors or protease inhibitors 
2. Pre-existing myelosuppression as defined as a total white blood cell count less than 4.0 K/uL, 
absolute neutrophil count less than 0.1 K/uL, absolute lymphocyte count less than 0.1 K/uL, or 
platelets less than 10 L/uL on routine pre-operative labs.  
3. Current use of clarithromycin, cyclosporine, atorvastatin, simvastatin, pravastatin, fluvastatin, 
gemfibrozil, fenofibrate, finofibric acid, and benzafibrate. 
4. Renal impairment as defined by serum creatinine greater than 3 times baseline or as deemed by 
the clinical inpatient team. 
5. Hepatic impairment as defined by serum transaminases greater than 3 times the upper limit of 
normal or as deemed by the clinical inpatient team 
6. Less than 20 months or greater than 5 years of age (5 years and 364 days). 
7. Children who weigh under 10 kilograms. 
8. Known allergic reactions to Colchicine 
9. Treatment with another investigational drug within 3 months  
10. Other conditions or postoperative complications that would increase the risk to the patient as 
determined by the study team, including but not limited to need for mechanical support 
(ECMO), or need for re-intervention within their chest more than 4 hours after arrival to the ICU. 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
Not applicable 
 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently entered in the study. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any serious 
adverse event (SAE). 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) will not be 
rescreened, as it would be a change in their postoperative clinical course such that they would be 
ineligible to receive the study intervention. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
• 
Target study sample size: 25 patients undergoing Fontan palliation. Anticipated number to be 
screened is 45 patients (assuming approximately 70% consent to the study). 
• 
Anticipated accrual rate: The Fontan operation typically occurs between the calendar months of 
March through October. The study will likely reach its target sample size after 2 years of 
recruitment seasons based on the number of Fontan operations the University of Michigan 
Congenital heart center performs each year. 
• 
Anticipated number of sites: Subjects will be enrolled at the University of Michigan only, and will 
be having their operation at our institution.  

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• 
Source of participants: Eligible subjects will be determined by the surgical schedule. Patients will 
then be screened for inclusion criteria by the medical record as well as parental interview. 
Subjects parents will be called pre-operatively to discuss the trial. Informed consent documents 
will be sent to their home for review. Signatures will be obtained either at their pre-operative 
clinic visit or in the waiting room while their child is undergoing surgery. This will be completed 
within 3 weeks prior to enrollment.  
• 
Recruitment venues: as above. 
• 
How potential participants will be identified and approached: Potential candidates will be 
identified based on the surgical schedule. Any patient who is scheduled to have a Fontan 
operation will be eligible to be approached for screening. 
• 
Specific strategies that will be used to recruit and retain historically under-represented 
populations in order to meet target sample size and conform with the NIH Policy on Inclusion of 
Women and Minorities as Participants In Research Involving Human Subjects: Any patient who is 
scheduled to undergo the Fontan operation will be recruited/screened for the study. This 
includes males, females, and any ethnic group. 
• 
This study includes a vulnerable population: Children as part of the definition of the study 
inclusion criteria, the subject must be 20 months to 5 years and 364 days of age.  
Patients enrolled will receive a small toy and their family will receive a $25 gift card to Amazon. 
 
 
6 
STUDY INTERVENTION 
 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
Colchicine is an alkaloid approved in 1961 for the use in Familial Mediterranean Fever in adults and 
children 4 years of age or older. As described in section 2.2 and 2.3, it has been widely used for decades 
in other indications, such as Gout, recurrent pericarditis, pericardial effusions and other inflammatory 
diseases. This drug is commercially available and is approved in children 4 years and older.  
 
There is no control intervention. 
6.1.2 DOSING AND ADMINISTRATION 
Colchicine will be given on postoperative day 2. Colchicine will be given at 0.6 mg once daily for the 
duration of chest tube output plus an additional 24 hours after chest tube removal. It will be given in the 
morning with the 0900 medication administration or within 12 hours of that time. It does not need to be 
timed relative to a meal. There will be no dose escalation. If the patient has complaints or evidence of GI 
distress (as some patients are too young to voice complaints) or nausea out of proportion to the 
expected degree, or diarrhea for more than 24 hours, the dose will be reduced to 0.3 mg (1/2 tab) given 
once daily. If the GI distress out of the expected degree continues for more than 24 hours following that 
change, the medication will be stopped. Expected degree is defined as more than 2 x per day for more 
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If the patient has chylous fluid, there will be no change in continuation of colchicine. If the patient is 
deemed to have clinically significant renal or hepatic dysfunction (3x baseline creatinine or 2x upper 
limit of normal for AST/ALT), the drug will be discontinued. If there is evidence of blood dyscrasias on 
screening CBCs, as defined as 20% lower than the a total white blood cell count less than 4.0 K/uL, 
absolute neutrophil count less than 0.1 K/uL, absolute lymphocyte count less than 0.1 K/uL, or platelets 
less than 10 L/uL , the drug will be discontinued. Other signs of toxicity that may warrant dose reduction 
or discontinuation (per the label) if severe: neuropathy, purpura, rash, rhabdomyolysis, muscle pain or 
weakness. 
After initial chest tube removal, if a patient has re-accumulation such that a chest tube is replaced 
within 48 hours, Colchicine will be continued for the duration of the new chest tube plus an additional 
24 hours. 
 
The maximum duration of drug delivery will be 4 weeks, at which point it will be deemed treatment 
failure and the medication will be terminated. The minimum duration of drug delivery will be 2 days. 
 
The drug is formulated in 0.6mg tablets. The tablet will be dissolved in 2-3 mL of either water, juice 
(non-grapefruit containing) or milk to make a solution that is able to be given to children of this age.39,40 
This process will be performed per standard hospital procedures. The drug may NOT be crushed. The 
drug may be given via mouth, G-tube, NG tube, or NJ tube.  The drug will be prepared beside for 
immediate use (given within one hour). 
 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
The University of Michigan hospital inpatient pharmacy will distribute the medication from their 
inpatient supply in pill format with instructions on creating the appropriate solution. The bedside nurse 
will dissolve the tablet in solution, and administer the medication.  
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Distributed by: 
Prasco Laboratories 
Mason, OH 45040   
Colchicine tablets, USP, 0.6 mg, are purple, capsule-shaped, film-coated tablets, scored on one side 
and debossed with “AR;374” on the other side. There is no control product. 

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6.2.3 PRODUCT STORAGE AND STABILITY 
 
Store Colchicine Tablets, USP at room temperature between 68°F and 77°F (20°C and 25°C). Keep 
Colchicine Tablets, USP in a tightly closed container. Keep Colchicine Tablets, USP out of the light. 
 
6.2.4 PREPARATION 
 
The drug is formulated in 0.6mg tablets. The tablet will be dissolved in 2-3 mL of either water, juice 
(non-grapefruit containing) or milk to make a solution that is able to be given to children of this age.39,40 
This process will be performed per standard hospital procedures. The drug may NOT be crushed. The 
drug may be given via mouth, G-tube, NG tube, or NJ tube.  The drug will be prepared beside for 
immediate use (given within one hour). 
 
 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
This study is neither blinded nor randomized. It is a single arm trial.  
 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
The study intervention will be completed entirely during a patient’s hospitalization, and therefore will 
be documented and monitored by the study team. If a dose is missed, i.e. due to vomiting, refusal, 
missed administration, etc., the dose will be logged as missed and dosing will resume the following day. 
 
6.5 
CONCOMITANT THERAPY 
 

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Patients will be screened at this study’s initiation. If the patient has been on a study drug in the 3 
months prior to the start of this trial, they will be excluded. As mentioned in section 5.2, concomitant 
use of atorvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, gemfibrozil, fenofibrate, fenofibric 
acid or benzafibrate (themselves associated with myotoxicity) or cyclosporine with colchicine may 
potentiate the development of myopathy and therefore patients taking these medications will be 
excluded.  
 
If it is imperative that a subject begin taking the following excluded medications such as drugs known to 
inhibit CYP34A and P-glycoprotein during the study, they will then be withdrawn from the study. 
 
Grapefruit and grapefruit juice may also interact and should not be consumed during colchicine 
treatment. 
 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
Discontinuation from the drug administration and sample collection does not mean discontinuation 
from the study. The subject’s medical record information will continue to be collected and they will be 
included in the analysis. As stated in section 6.1.2, the medication dose will be cut in half in the event of 
GI complaints or symptoms above the expected degree and these will be reported as adverse events 
(AEs). If the patient continues to have GI complaints or symptoms (nausea, abdominal pain, diarrhea) 
above the expected degree, for more than 24 hours after dose decrease, the study drug will be 
discontinued and these will also be reported as AEs. 
 
Also as stated in section 6.1.2, If the patient is deemed to have renal or hepatic dysfunction on screening 
comprehensive metabolic panels, as defined by the clinical team or if the serum creatinine is greater 
than 3 times the baseline, or if the transaminases are 2 time higher than the upper limit of normal, the 
study drug will be discontinued. If there is evidence of blood dyscrasias on screening CBCs, as defined as 
a total white blood cell count less than 4.0 K/uL, absolute neutrophil count less than 0.1 K/uL, absolute 
lymphocyte count less than 0.1 K/uL, or platelets less than 10 L/uL , the drug will be discontinued and 
the finding will be reported as an adverse event (AE). If these laboratory abnormalities are not related or 
unlikely to be related to the study intervention as defined in section 8.3.3.2 and the abnormalities 
normalize within 48 hours, the study intervention may be restarted upon discussion with the clinical 
team and/or the safety monitoring board as necessary. 
 
Pleural samples will be discontinued and the drug will be discontinued in the event that a patient has a 
re-intervention in their chest (i.e. re-operation, chest exploration more than 4 hours after arrival in ICU). 
Re-placement of chest tubes is not included in the definition of re-intervention in a patient’s chest. 
Blood samples for screening purposes (see SOA in section 1.3) will be obtained as long as the patient is 
on the study drug.  
 

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There is no specific additional data that will need to be recorded at the time of study intervention 
discontinuation, aside from the medical record/history data already recorded as part of the study 
design. 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• 
Participant unable to receive the drug for 2 days despite continued chest tube drainage 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF). Subjects who sign the informed consent form but do not receive the study 
intervention may be replaced.  Subjects who sign the informed consent form and receive the study 
intervention, and subsequently withdraw, or are withdrawn or discontinued from the study will not be 
replaced. 
 
7.3 
LOST TO FOLLOW-UP 
 
 Not applicable. The study is during their inpatient postoperative hospital stay. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
 
The study intervention, Colchicine, will be given once for the duration of chest tube drainage plus 24 
hours after chest tube discontinuation, as described in Section 6.1.2. The medication will be put into 
solution (as described in Section 6.1.2) by the bedside registered nurse. 
 
Pleural fluid studies 
3 mL of pleural fluid will be collected from chest tubes in sterile fashion on postoperative days 1, 2, 3, 4, 
7, 10, 14, 21 and 28. The self-sealing chest tube will be cleaned with Betadine and a sterile needle no 
larger than 23G with a sterile syringe will be inserted into the tubing with negative pressure to collected 
the fluid.  Samples will be centrifuged at 500 RPM x 5 minutes, the supernatant will be collected and 
placed into a storage tube, and then frozen at -80 degrees Celsius until all samples are collected.  At that 
time, all samples will be analyzed concurrently to decrease variability in laboratory technique. Pleural 
fluid will be tested using the Bio-rad Bio-Plex ProHuman Cytokine 17-plex Assay (#M5000031YV) on the 

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Bio-Rad MAGPIX Multiplex Reader41 for the following inflammatory cytokines42: IL-1β, IL-2, IL-4, IL-5, IL-
6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17A, TNF-α,  granulocyte macrophage colony-stimulating factor (GM-
CSF), granulocyte-colony stimulating factor (G-CSF), interferon-gamma (IFN-γ), monocyte 
chemoattractant protein (MCP-1), and macrophage inflammatory protein (MIP-1β). 
 
Samples will also be obtained if the clinical team deems the pleural fluid “chylous” prior to initiation of 
standard of care therapya. If a patient is started on standard of care treatment for high-output effusions, 
one additional sample will be obtained on the day of therapy initiation if not on the prior collection 
schedule, and then the protocol will revert to the prior collection schedule.  
 
If a patient has chest tubes replaced for re-accumulation of pleural fluid, samples will be collected on 
the day of placement, for the first 3 days, and then weekly thereafter.  
 
Blood studies 
A complete blood count and comprehensive metabolic panel will be obtained on post-operative days as 
described in Section 1.3 (SoA). The CBCs will be run at the CLIA certified hospital laboratory to decrease 
variability.  
 
All blood samples and pleural fluid samples will be collected by a registered nurse, physician, or 
phlebotomist.  
 
aStandard of Care therapy 
If a patient has chylous output at any time upon initiation of enteral nutrition as defined by the clinical 
team (testing fluid for triglycerides is variable by clinician and there is no clear standard definition), 
standard of care protocol will be followed and colchicine will be continued. If a patient has high-output 
effusions > 20 mL/kg/day continuing on POD 5 that are not deemed clinically “chylous,” the high-output 
protocol will be followed (see protocol for institutional standard of care flowsheet below). One 
additional sample will be obtained on the day of therapy initiation if not on the prior collection 
schedule, and then the protocol will revert to the prior collection schedule. 
 

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Patient data 
Patient demographics will be collected including age, ethnicity, and admission weight and height. Any 
chromosomal abnormality or other organ anomaly will be noted. The cardiac diagnosis will be recorded 
with special attention to ventricular morphology. Preoperative echocardiogram findings will be 

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recorded, especially ventricular function and atrioventricular valve regurgitation. Preoperative heart 
catheterization data will be recorded when available including ventricular end-diastolic pressure, 
pulmonary artery pressure, and transpulmonary gradient pressure. 
 
Intraoperative data to be collected include the surgical procedure and bypass, cross clamp, and deep 
hypothermic arrest times. Any need for intraoperative steroids will be noted. 
 
In the postoperative course, total daily pleural fluid output, total chest tube days, and presence of chyle 
will be recorded. The total ventilator time, hospital time, and daily maximum vaso-inotropic score will 
be recorded.43  Post-operative steroids and duration of therapy will be recorded. Administration of 
NSAIDs or spironolactone will be noted. Any complications will be recorded including need for 
extracorporeal membrane oxygenation (ECMO), renal replacement therapy (RRT), infection, unplanned 
surgical procedure or catheterization, cardiopulmonary resuscitation, and death. Finally, treatment for 
pleural drainage will be documented including low fat diet, need for periods of NPO with total 
parenteral nutrition, octreotide infusion, thoracic duct ligation, and pleurodesis. 
 
The bedside nurse or study staff will complete an AE survey for the patient regarding GI complaints at 24 
and 48 hours post initiation of study intervention and weekly thereafter. 
 
The patient will have standard post-operative clinical care. 
 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
Serum creatinine will be obtained within 30 days preoperatively via a renal function panel as part of the 
standard of care pre-operative screening. If, after surgery, the patient is unstable; i.e. needs mechanical 
support (ECMO) or re-exploration greater than 4 hours after surgery, the patient will not be a candidate 
for the study and will not have samples collected or receive the study intervention. Two milliliters of 
blood will be obtained for CBC/comprehensive metabolic panel as described in Section 1.3 and 8.1. CBCs 
and comprehensive metabolic panels will be obtained as indicated in Section 1.3 and if blood dyscrasias, 
renal impairment or liver impairment are noted as described in section 6.1.2, the study drug will be 
discontinued. If these abnormalities are not or unlikely to be related to the study intervention and 
resolve within 48 hours, the study drug may be restarted as described in section 7.1. GI complaints will 
be monitored as described in Section 1.3 and if present out of proportion to the expected degree, study 
drug dose will be decreased or stopped as described in section 6.1.2. The CLIA certified hospital 
laboratory will perform these laboratory analyses. If the patient develops hives, rash, or anaphylaxis, the 
study intervention will be discontinued. 
 
Pleural Samples will be obtained via semi-sterile technique as described in section 8.1. Diagnosis of 
infection will be monitored as described in Section 1.3. If a patient has diagnosed infection by the clinical 
team, either surgical site, blood, or urine, this will be noted as an adverse event.  
 
All surveys and laboratory samples will be collected by a registered nurse or physician. 
 
If a patient is deemed to have a blood dyscrasia, elevation in creatinine or transaminases requiring 
discontinuation of the study intervention, a repeat CBC or comprehensive metabolic panel, whichever is 
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has GI complaints requiring discontinuation, symptoms will be monitored for 2 days following the last 
dose to ensure resolution.   
 
Medical chart review will be performed and specific data recorded as described in Section 8.1.  
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
 
8.3.3 Classification of an Adverse Event 
 
8.3.3.1 SEVERITY OF EVENT 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 

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All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study intervention (dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within 
a reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
study intervention) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician.] 
 
 
8.3.3.3 EXPECTEDNESS  
 
The safety monitoring committee (SMC), made up of a physician, Adult-Congenital Cardiologist, who has 
had experience managing postoperative Fontan patients as well as experience using colchicine in a 
clinical environment, and a nurse practitioner in Pediatric Cardiology who works extensively with the 
Fontan population and is actively involved in multiple ongoing research studies will be responsible for 
determining whether an adverse event (AE) is expected or unexpected based on the approved drug 
label and the informed consent document.  Neither the physician nor the NP are part of the study team. 
An AE will be considered unexpected if the nature, severity, or frequency of the event is not consistent 
with the risk information previously described for the study intervention. The SMC will meet once every 
4 months to review all AEs and SAEs, unless there have been fewer than 5 new patients enrolled, at 
which time that meeting can be postponed to the next scheduled meeting time. 
 

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8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during hospitalization and interviews of a study participant parents or guardians 
presenting for medical care, or upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
Principal investigator or nurse coordinator will record all reportable events with start dates occurring 
any time the first sample is obtained until 7 days after the last day of dosing of the study drug.  This will 
be determined by a follow up phone call 5-14 days after the last day of dosing of the study drug. Events 
will be followed for outcome information until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
 
We will report all AEs to our SMC and our institution’s IRB as per the IRBMED reporting guidelines. The 
principal investigator is responsible for completing a CRF and signing off on all serious AEs. The PI or the 
nurse coordinator will be responsible for completing a CRF and signing off on all moderate or mild AEs. 
Serious AEs will be reported to the PI within 24 hours of occurrence. Moderate AEs will be reported to 
the PI within 3 days of occurrence to the PI, and mild AEs will be reported within 1 week to the PI. The 
SMC will review all AEs every 4 months unless there have been fewer than 5 new patients enrolled, at 
which time that meeting can be postponed to the next scheduled meeting time. 
 
Any surgically-related complications and post-operative complications that occur prior to initiation of 
the study intervention will not be repor 
ted per the standard process for reporting. These complications will be recorded in our study database 
as post-operative complications.  
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
AEs and SAEs will be reported to the IRB as per their SAE reporting guidelines. Study endpoints that are 
serious adverse events (e.g., all-cause mortality) must be reported in accordance with the protocol 
unless there is evidence suggesting a causal relationship between the study intervention and the event 

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(e.g., death from anaphylaxis). In that case, the investigator must immediately report the event to the 
IRB. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting documentation 
of the event may be requested by the SMC and should be provided as soon as possible. 
 
This study will comply with all applicable regulations found in 21 CFR 312.32.  
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
Parents or guardians of participants will be notified regarding any serious AE felt by the SMC to be 
definitely related to the study intervention. In the event that routine safety monitoring laboratory 
results have values out of range, this will be discussed with the inpatient clinical team.  
 
 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2 UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the principal investigator (PI). The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 

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To satisfy the requirement for prompt reporting, UPs will be reported per the IRB requirements.   
 
 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
• 
Primary Efficacy Endpoint: Change in Cytokine concentrations (TNF-α) from POD 1 to DMD in 
pleural fluid  
 
Change in TNF-α (ChangeTNFα) in pleural fluid will be calculated as: 
 
ChangeTNFα= TNFαPOD1 - TNFαDMD 
 
The calculated change in TNF-α in Fontan patients treated with Colchicine (ChangeTNFαColchicine) 
will be compared with a historical cohort of Fontan patients (ChangeTNFαControl)  
 
The null and alternative hypotheses for the primary endpoint will be as following: 
 
H0: ChangeTNFαColchicine = ChangeTNFαControl    vs.    Ha: ChangeTNFαColchicine ≠ ChangeTNFαControl 
 
 
• 
Secondary Efficacy Endpoint(s): 
o Cytokine concentrations (particularly TNF-α, MIP-1βm, IL-17A, IL-8, and INF-γ) at a given 
time-point postoperatively 
 
Each cytokine concentration in Fontan patients treated with Colchicine will be measured 
at a given postoperative time point (ex. TNFαColchicine_ti) and will be compared with a 
historical cohort of Fontan patients not treated with Colchicine (ex. TNFαControl ti)       
 
The null and alternative hypotheses for the secondary endpoint (1) will be as following: 
 
H0: TNFαColchicine_ti = TNFαControl ti_    vs.    Ha: TNFαColchicine_ti ≠ TNFαControl ti, ti = POD 1, POD 2, ⋯ , DMD_     
 
o Duration of pleural drainage in days, from date of Fontan surgery to chest tube drainage 
discontinuation  
   
Duration of pleural drainage (DaysPleuralDrain) will be calculated as: 
 
DaysPleuralDrain = Date of chest tube drainage discontinuation – Date of Fontan surgery 
 
The calculated duration of pleural drainage in Fontan patients treated with Colchicine 
(DaysPleuralDrainColchicine) will be compared with a historical cohort of Fontan patients 
(DaysPleuralDrainControl)  
 

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The null and alternative hypotheses for the secondary endpoint (2) will be as following: 
 
H0: DaysPleuralDrainColchicine = DaysPleuralDrainControl    vs.    Ha: DaysPleuralDrainColchicine ≠ 
DaysPleuralDrainControl 
 
o Hospital length of stay in days, from date of Fontan to hospital discharge date 
 
Postoperative hospital length of stay (HospitalLOS) will be calculated as: 
 
HospitalLOS = Date of hospital discharge - Date of Fontan surgery 
 
The calculated hospital length of stay in Fontan patients treated with Colchicine 
(HospitalLOSColchicine) will be compared with a historical cohort of Fontan patients 
(HospitalLOSControl)  
 
The null and alternative hypotheses for the secondary endpoint (3) will be as following: 
 
H0: HospitalLOSColchicine = HospitalLOSControl    vs.    Ha: HospitalLOSColchicine ≠ HospitalLOSControl 
 
 
9.2 
SAMPLE SIZE DETERMINATION 
To determine if Colchicine is associated with decreased inflammatory cytokines (TNF-α) within the 
pleural space in postoperative Fontan patients compared to a historical cohort of Fontan patients, 
change in TNF-α from POD 1 to DMD in pleural fluid in the Fontan patients treated with Colchicine will 
be compared to a historical cohort of Fontan patients, using two-sample t-test or Wilcoxon rank sum 
test. Our original Fontan study demonstrated that pleural TNF-α in Fontan patients were significantly 
increased from POD 1 to DMD (n=25; median 30.29 to 66.97, p<.0001)17. Assuming its median TNF-α 
change from POD 1 to DMD (32.02) and range/4 of TNF-α at POD 1 (16.91) as mean and estimated 
standard deviation of change in TNF-α from a historical cohort of Fontan patients, sample size estimate 
was calculated using PASS 11 (Kaysville, UT)  as follows;44 
A sample size of 25 Fontan patients treated with Colchicine is required to achieve at least 80% power to 
detect a 45% or greater decrease in TNF-α at DMD from POD 1 compared to a historical cohort of 
Fontan patients, based on two-sided 0.05 significance level using two-sample t-test. As described in 
Section 5.5, anticipated number to be screened is 45 patients during the study period. Assuming 
approximately 70% consent to the study, enrolling 25 Fontan patients will be feasible.          
9.3 
POPULATIONS FOR ANALYSES 
Patients undergoing Fontan operation ages of 20 months -5 years at the University of Michigan 
Congenital Heart Center will be included in the analysis. The analysis will be based on an Intention-to-
Treat (ITT) approach. 
 
9.4 
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9.4.1 GENERAL APPROACH 
All analyses will be performed using SAS version 9.4 (SAS Institute, Cary, NC, USA), with statistical 
significance level of 0.05 using two-sided tests. Descriptive statistics of demographic and clinical 
characteristics will be presented as frequency and percentage (%) for categorical variables, and mean and 
standard deviation (SD) or median and interquartile range (IQR), depending on distributional assumption, 
for continuous variables. A detailed statistical analysis plan for each specific aim will be described in the 
sections below. 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
The primary endpoint of the study is change in Cytokine concentrations (TNF-α) from POD 1 to DMD in 
pleural fluid. As described in section 9.1, change in TNF-α (ChangeTNFα) in pleural fluid will be 
calculated as: 
ChangeTNFα= TNFαPOD1 - TNFαDMD 
The calculated change of TNF-α in patients s/p Fontan palliation treated with Colchicine will be reported 
as mean and SD or median and IQR, as appropriate, and will be compared with a historical cohort of 
Fontan patients using two-sample t-test or Wilcoxon rank sum test.  
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
The secondary endpoints are:  
1. Cytokine concentrations (particularly TNF-α, MIP-1βm, IL-17A, IL-8, and INF-γ) at a given time-
point postoperatively 
 
Each cytokine concentration measured at a given postoperative time point in Fontan patients 
treated with Colchicine will be reported as mean and SD or median and IQR, as appropriate, and 
will be compared with a historical cohort of Fontan patients not treated with Colchicine at the 
corresponding postoperative time-point, using two-sample t-test or Wilcoxon rank sum test.  
2. Duration of pleural drainage in Fontan patients treated with Colchicine 
Duration of pleural drainage in days, from date of Fontan surgery to chest tube drainage 
discontinuation in Fontan patients treated with Colchicine will be calculated and reported as 
median and IQR and compared with a historical cohort of Fontan patients using Wilcoxon rank 
sum test.    
3. Hospital length of stay in Fontan patients treated with Colchicine 
Hospital length of stay in days will be calculated from date of Fontan surgery to hospital 
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calculated hospital length of stay in Fontan patients treated with Colchicine will be compared to 
a historical cohort of Fontan patients, using Wilcoxon rank sum test.    
 
9.4.4 SAFETY ANALYSES 
Each AE described in Section 7 and 8 will be reported including start date/time, stop date/time, severity, 
and duration. Frequency and severity of AEs will be presented using summary statistics. Adverse events 
leading to premature discontinuation from the study intervention and serious treatment-emergent AEs 
will be listed in a table.  
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
Baseline characteristics, including demographics and pre- and intra-operative characteristics, will be 
compared between Fontan patients with Colchicine and a historical cohort of Fontan patients, using Chi-
square test or Fisher’s exact test for categorical variables and two-sample t-test or Wilcoxon rank sum 
test for continuous variables, as appropriate. 
 
9.4.6 PLANNED INTERIM ANALYSES  
There will be an interim analysis after 9 patients have been enrolled (5 patients completing the full 
course of treatment). This will entail simple descriptive statistics and will not alter the remainder of the 
study design or power calculations. 
 
9.4.7 SUB-GROUP ANALYSES 
No sub-group analyses are planned due to small number of sample size anticipated. 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
No tabulation of individual participant data is planned. Instead, each cytokine data for individual 
participant will be graphically presented over time point.   
 
9.4.9 EXPLORATORY ANALYSES 
In addition to the individual participant data, summary statistics (such as mean or median, as 
appropriate) of each cytokine data will be also graphically presented over time point.   
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to administering study 

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intervention.  The following consent materials are submitted with this protocol : Informed Consent 
document. 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the parent/guardian of the participant will be asked to read and 
review the document. The investigator will explain the research study to the parent/guardian of the 
participant and answer any questions that may arise. A verbal explanation will be provided in terms 
suited to the parent/guardian’s comprehension of the purposes, procedures, and potential risks of the 
study and of their rights as research participants.  The parent/guardian of the participants will have the 
opportunity to carefully review the written consent form and ask questions prior to signing. The 
parent/guardian of the participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The parent/guardian of the participant will 
sign the informed consent document prior to any procedures being done specifically for the study.  
Parent/guardians of the participants must be informed that participation is voluntary and that they may 
withdraw from the study at any time, without prejudice. A copy of the informed consent document will 
be given to the parent/guardian of the participants for their records. The informed consent process will 
be conducted and documented in the source document (including the date), and the form signed, 
before the participant undergoes any study-specific procedures. The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their medical care will not be 
adversely affected if they decline to participate in this study. 
 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigator and regulatory 
authorities.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform study participants, the Institutional Review Board (IRB), and will provide the reason(s) 
for the termination or suspension.  Study participants will be contacted, as applicable, and be informed 
of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
 
 

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10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and their interventions. This confidentiality is extended to cover testing of biological samples and 
genetic tests in addition to the clinical information relating to participants. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party without 
prior written approval of the investigator.  
 
All research activities will be conducted in as private a setting as possible. 
 
Authorized representatives of the investigator, representatives of the Institutional Review Board (IRB), 
regulatory agencies or pharmaceutical company supplying study product may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical study site 
will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be stored in the University of Michigan secure network drive. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study management 
systems used by clinical sites and by the University of Michigan research staff will be secured and 
password protected. At the end of the study, all study databases will be de-identified and archived at 
the University of Michigan. 
 
A Certificate of Confidentiality is not applicable. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
Data collected for this study will be analyzed and stored at the University of Michigan server and will be 
monitored and maintained by the Michigan Congenital Heart Outcomes Research and Discovery 
(MCHORD) program. 
 
With the participant’s approval and as approved by local Institutional Review Boards (IRBs), de-
identified biological samples will be stored at the University of Michigan laboratory. These samples 
could be used to research the causes of prolonged pleural drainage in postoperative Fontan patients, its 
complications and other conditions for which individuals with Fontan physiology are at increased risk, 
and to improve treatment.  will also be provided with a code-link that will allow linking the biological 
specimens with the phenotypic data from each participant, maintaining the blinding of the identity of 
the participant. 
 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
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When the study is completed, access to study data and/or samples will be provided through the 
MCHORD program. 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Co-Principal Investigator 
Albert Rocchini, MD, Professor 
Stephanie Goldstein, MD, Fellow 
University of Michigan 
University of Michigan  
1540 E. Hospital Dr. 
Ann Arbor, MI 48109 
1540 E. Hospital Dr 
Ann Arbor, MI 48105 
734-763-6242 
734-936-8765 
rocchini@med.umich.edu 
stablowz@med.umich.edu 
 
 
 
 
 
10.1.6 SAFETY OVERSIGHT 
Safety oversight will be under the direction of a Safety Monitoring Committee (SMC) composed of 
individuals with the appropriate expertise, including a nurse practitioner and a physician who are each 
independent investigators and experts in the field of pediatric cardiology with an emphasis on Fontan 
physiology and long term outcomes. The SMC will meet at least quarterly, unless there have been fewer 
than 5 new patients enrolled, at which time that meeting can be postponed to the next scheduled 
meeting time, to assess safety and efficacy data. Prior to the initiation of the study, each data element 
that the SMC needs to assess will be clearly defined. The SMC will provide its input to IRB as indicated. 
 
10.1.7 CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).  
 
• 
The Co-Principal Investigator will conduct the monitoring of the data collection or will collect 
the data herself. Monitoring will occur bi-weekly in the format of either on-site meeting or via 
teleconference with the study team data collectors. There will be 100% data verification.  
 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan will be 
developed to describe a site’s quality management. 
 

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Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is 
conducted and data are generated and biological specimens are collected, documented (recorded), and 
reported in compliance with the protocol, International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)).  
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.   
 
Hardcopies of the AE surveys will be provided for use as source document worksheets for recording data 
for each participant enrolled in the study.  Data recorded in the electronic case report form (eCRF) 
derived from source documents should be consistent with the data recorded on the source documents.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into RedCAP, a 21 CFR Part 11-compliant data capture 
system provided by the The University of Michigan. The data system includes password protection and 
internal quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate. Clinical data will be entered directly from the source documents. 
 
10.1.9.2 STUDY RECORDS RETENTION  
 
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Conference on Harminosation (ICH) region and until there are no pending 
or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study intervention. These documents should be 
retained for a longer period, however, if required by local regulations. No records will be destroyed 
without the written consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform 
the investigator when these documents no longer need to be retained. 
 
 

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10.1.10 
PROTOCOL DEVIATIONS  
 A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 7 working days of identification of the protocol deviation, or within 7 working days of 
the scheduled protocol-required activity.  All deviations must be addressed in study source documents.  
Protocol deviations must be sent to the reviewing Institutional Review Board (IRB) per their policies. The 
site investigator is responsible for knowing and adhering to the reviewing IRB requirements. Further 
details about the handling of protocol deviations will be included in the MOP. 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals.  Data from this study may be requested from other researchers x years after the 
completion of the primary endpoint by contacting Stephanie Goldstein. 
 
In addition, this study will comply with the NIH Genomic Data Sharing Policy, which applies to all NIH-
funded research that generates large-scale human or non-human genomic data, as well as the use of these 
data for subsequent research. Large-scale data include genome-wide association studies (GWAS), single 
nucleotide polymorphisms (SNP) arrays, and genome sequence, transcriptomic, epigenomic, and gene 
expression data. 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study 

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leadership has established policies and procedures for all study group members to disclose all conflicts 
of interest and will establish a mechanism for the management of all reported dualities of interest. 
 
10.2 ADDITIONAL CONSIDERATIONS 
Not applicable. 
 
 
 

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10.3 ABBREVIATIONS 
The list below includes abbreviations utilized in this template.  However, this list should be customized for 
each protocol (i.e., abbreviations not used should be removed and new abbreviations used should be 
added to this list). 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CBC 
Complete blood count 
CLIA 
Clinical Laboratory Improvement Amendments 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DMD 
Day most distal 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FMF 
Familial Mediterranean Fever 
G-CSF 
Granulocyte-Colony Stimulating Factor 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practices 
GM-CSF 
Granulocyte Macrophage-Colony Stimulating Factor 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
ICH 
International Conference on Harmonisation  
IDE 
Investigational Device Exemption 
IL 
Interleukin 
IND 
Investigational New Drug Application 
INF 
Interferon  
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ITT 
Intention-To-Treat 
MCP 
Monocyte Chemoattactant Protein 
MIP 
Macrophage Inflammatory Protein 
MOP 
Manual of Procedures 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
NPO 
Nil per os 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
POD 
Postoperative day 
QA 
Quality Assurance 
QC 
Quality Control 
RV 
Right Ventricle 
SAE 
Serious Adverse Event 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
TNF 
Tumor Necrosis Factor 

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UP 
Unanticipated Problem 
US 
United States 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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