CPFP: Colchicine in Postoperative Fontan Patients

• Sponsor: University of Michigan (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03575572
• Collaborator: (none)
• Enrollment: 11
• Location: 1
• Arm: 1
• Actual Duration (Months): 28.5
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The investigators found that there is inflammation in the chest drainage in patients after the Fontan operation. The investigators want to test the theory that Colchicine, an anti- inflammatory medication, can decrease the inflammation in the chest tube drainage after the Fontan operation, and can decrease the amount of time that patients having this surgery will have drainage.

Condition or Disease	Intervention/Treatment	Phase
Single-ventricle; Heart Diseases	Drug: Colchicine	Phase 2/Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 11 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Colchicine in Postoperative Fontan Patients (CPFP)
• Actual Study Start Date: Aug 29, 2018
• Actual Primary Completion Date: Jan 13, 2021
• Actual Study Completion Date: Jan 13, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Colchicine 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.	Drug: Colchicine; Colchicine is an alkaloid approved in 1961 for the use in Familial Mediterranean Fever in adults and children 4 years of age or older. 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.

Outcome Measures

Primary Outcome Measures

1. Change in Cytokine Total Mass in Pleural Fluid From Patients Treated With Colchicine [Postoperative day 1 ; day most distal from surgery, approximately 7 days after surgery]

   Cytokine total mass measured by the Bio-rad Bio-Plex ProHuman Cytokine 17-plex Assay.

2. Difference in Change of Cytokine Concentrations in Pleural Fluid Patients Treated With Colchicine Compared to Historical Controls [Postoperative day 1 ; day most distal from surgery, approximately 7 days after surgery]

   Difference is shown via two columns of separate data, but given that enrollment didn't meet target before termination statistical analysis was not done for this measure

Secondary Outcome Measures

1. Cytokine Total Mass as Measured in Postoperative Fontan Patients Treated Empirically With Colchicine [Postoperative days 1, 2, 3, 4, 7]

   Particularly Cytokine total mass of TNF-α, MIP-1β, IL-8, and IL-10, determined by the Bio-rad Bio-Plex ProHuman Cytokine 17-plex Assay Data was only collected while patients had chest tubes in place (up to 7 days only)

2. Difference in Cytokine Total Mass, as Measured in Postoperative Fontan Patients Treated Empirically With Colchicine in Comparison to a Cohort of Postoperative Fontan Patients [Postoperative days 1, 2, 3, 4, 7, 10]

   Cytokine total mass measured by Bio-rad Bio-Plex ProHuman Cytokine 17-plex Assay Data was only collected from Colchicine patients while they had chest tubes in place (up to 7 days). For historical controls data was collected up through Day 10

3. Duration of Pleural Drainage as Measured in Postoperative Fontan Patients Treated Empirically With Colchicine [Date of chest tube drainage discontinuation, approximately 11 days after surgery]

   Duration is measured in days, from date of Fontan surgery to chest tube drainage discontinuation.

4. Difference of Duration of Pleural Drainage of Two Groups, in Empiric Treatment With Colchicine Compared to a Cohort of Fontan Patients Not Treated With Colchicine [Date of chest tube drainage discontinuation, approximately 11 days after surgery]

   Duration is measured in days, from date of Fontan surgery to chest tube drainage discontinuation

5. Hospital Length of Stay as Measured in Postoperative Fontan Patients Treated Empirically With Colchicine [Hospital discharge at study completion, approximately 2 weeks after surgery]

   Measured in days, from date of Fontan surgery to chest tube drainage discontinuation

6. Difference in Hospital Length of Stay [Hospital discharge at study completion, approximately 2 weeks after surgery]

   Measured in days compared to historical controls

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Months to 5 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Ages 20 months to 5 years and 364 days are eligible

• Diagnosed with single ventricle heart disease requiring Fontan palliation

• Undergoing Fontan palliation at the University of Michigan Congenital Heart Center

• Ability to take oral or enteral medication

Exclusion Criteria:

• Treatment with another investigational drug within 3 months

• Pre-existing myelosuppression or decreased bone marrow activity.

• Current or recent treatment with certain drugs

• Renal or hepatic impairment deemed by the study team

• Conditions and/or post-operative complications that would increase risk to the patient such as mechanical support (ECMO) or issues in the intensive care unit (ICU)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Michigan	Ann Arbor	Michigan	United States	48109

Sponsors and Collaborators

• University of Michigan

Investigators

• Principal Investigator: Stephanie Goldstein, MD, University of Michigan

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 6, 2020

More Information

Publications

None provided.

• Responsible Party: Stephanie Goldstein, House Officer, Pediatric Cardiology and House Officer, Pediatric Critical Care (during active trial status), University of Michigan
• ClinicalTrials.gov Identifier: NCT03575572
• Other Study ID Numbers: HUM00143571
• First Posted: Jul 2, 2018
• Last Update Posted: May 9, 2022
• Last Verified: Apr 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Stephanie Goldstein, House Officer, Pediatric Cardiology and House Officer, Pediatric Critical Care (during active trial status), University of Michigan: Fontan; Colchicine; heart surgery
• Additional relevant MeSH terms: Heart Diseases; Univentricular Heart; Colchicine

Study Results

Participant Flow

Pre-assignment Detail	2 people who were consented didn't actually begin the trial. Under the protocol, historical controls were not considered enrolled in this study, so they are not included in participant flow. Historical control data were taken from an observational study with no intervention that was published prior to first enrollment in this trial. Data on the historical controls are available at PMID: 30710164.

Arm/Group Title	Colchicine
Arm/Group Description	All patients entered the intended protocol where Colchicine was empirically given 0.6mg once daily to postoperative Fontan patients starting on postoperative day 2 and ending 1 day after chest tubes were removed or for a maximum of 4 weeks.
Period Title: Overall Study
STARTED	9
COMPLETED	5
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Colchicine	Historical Controls	Total
Arm/Group Description	All patients entered the intended protocol where Colchicine was empirically given 0.6mg once daily to postoperative Fontan patients starting on postoperative day 2 and ending 1 day after chest tubes were removed or for a maximum of 4 weeks.	Historical Controls were post-operative Fontan patients who underwent their operation at the University of Michigan. They were part of a prospective observational study that was published in 2019 which included the chest tube drainage sample collection similar to that done with the Colchicine cohort in this trial.	Total of all reporting groups
Overall Participants	9	25	34
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	2.7	2.5	NA
Sex: Female, Male (Count of Participants)
Female	5 55.6%	7 28%	12 35.3%
Male	4 44.4%	18 72%	22 64.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 11.1%	0 0%	1 2.9%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 11.1%	0 0%	1 2.9%
White	6 66.7%	22 88%	28 82.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 11.1%	3 12%	4 11.8%
Region of Enrollment (participants) [Number]
United States	9 100%	25 100%	34 100%
Primary Diagnosis (participants) [Number]
Hypoplastic left heart syndrome (HLHS)	6 66.7%	14 56%	20 58.8%
Not HLHS	3 33.3%	11 44%	14 41.2%

Outcome Measures

1. Primary Outcome

Title	Change in Cytokine Total Mass in Pleural Fluid From Patients Treated With Colchicine
Description	Cytokine total mass measured by the Bio-rad Bio-Plex ProHuman Cytokine 17-plex Assay.
Time Frame	Postoperative day 1 ; day most distal from surgery, approximately 7 days after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colchicine Per Protocol
Arm/Group Description	All patients entered the intended protocol where Colchicine was empirically given 0.6mg once daily to postoperative Fontan patients starting on postoperative day 2 and ending 1 day after chest tubes were removed or for a maximum of 4 weeks. These participants completed the protocol.
Measure Participants	5
Interleukin (IL)-8; post op. Day 1	60925.8
IL-8, Day 7	8684.57
Tumor Necrosis Factor (TNF)-alpha, Day 1	6552.7
TNF-alpha, Day 7	694.575
Macrophage Inflammatory Protein (MIP)-1 Beta Day 1	4949.89
MIP-1 Beta Day 7	247.775
Interleukin (IL)-10 Day 1	5286.55
IL-10 Day 7	132.755

2. Primary Outcome

Title	Difference in Change of Cytokine Concentrations in Pleural Fluid Patients Treated With Colchicine Compared to Historical Controls
Description	Difference is shown via two columns of separate data, but given that enrollment didn't meet target before termination statistical analysis was not done for this measure
Time Frame	Postoperative day 1 ; day most distal from surgery, approximately 7 days after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colchicine	Historical Controls
Arm/Group Description	All patients entered the intended protocol where Colchicine was empirically given 0.6mg once daily to postoperative Fontan patients starting on postoperative day 2 and ending 1 day after chest tubes were removed or for a maximum of 4 weeks. These participants completed the protocol.	Historical Controls were post-operative Fontan patients who underwent their operation at the University of Michigan. They were part of a prospective observational study that was published in 2019 which included the chest tube drainage sample collection similar to that done with the Colchicine cohort in this trial.
Measure Participants	5	25
IL-8 Day 1	60925.80	83263.45
IL-8 Day 7	8684.57	64695.50
TNF-Alpha Day 1	6552.70	8080.38
TNF-ALpha Day 7	694.575	3320.97
MIP-1 Beta Day 1	4949.89	11527.80
MIP-1Beta Day 7	247.775	5986.4
IL-10, Day 1	5286.55	14474.4
IL-10, Day 7	132.755	885.04

3. Secondary Outcome

Title	Cytokine Total Mass as Measured in Postoperative Fontan Patients Treated Empirically With Colchicine
Description	Particularly Cytokine total mass of TNF-α, MIP-1β, IL-8, and IL-10, determined by the Bio-rad Bio-Plex ProHuman Cytokine 17-plex Assay Data was only collected while patients had chest tubes in place (up to 7 days only)
Time Frame	Postoperative days 1, 2, 3, 4, 7

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colchicine Per Protocol
Arm/Group Description	All patients entered the intended protocol where Colchicine was empirically given 0.6mg once daily to postoperative Fontan patients starting on postoperative day 2 and ending 1 day after chest tubes were removed or for a maximum of 4 weeks. These participants completed the protocol.
Measure Participants	5
IL-8 Day 1	60925.80
IL 8 Day 2	22178.00
IL 8 Day 3	26837.20
IL 8 Day 4	50895.36
IL 8 Day 7	8684.57
IL 10 Day 1	5286.55
IL 10 Day 2	2788.44
IL 10 Day 3	586.50
IL 10 Day 4	448.06
IL 10 Day 7	132.755
TNF Alpha Day 1	6552.70
TNF Alpha Day 2	6220.50
TNF Alpha Day 3	3791.84
TNF Alpha Day 4	2517.90
TNF Alpha Day 7	694.575
MIP-1 Beta Day 1	4949.89
MIP-1 Beta Day 2	3066.80
MIP-1 Beta Day 3	4031.04
MIP-1 Beta Day 4	2730.50
MIP-1 Beta Day 7	247.775

4. Secondary Outcome

Title	Difference in Cytokine Total Mass, as Measured in Postoperative Fontan Patients Treated Empirically With Colchicine in Comparison to a Cohort of Postoperative Fontan Patients
Description	Cytokine total mass measured by Bio-rad Bio-Plex ProHuman Cytokine 17-plex Assay Data was only collected from Colchicine patients while they had chest tubes in place (up to 7 days). For historical controls data was collected up through Day 10
Time Frame	Postoperative days 1, 2, 3, 4, 7, 10

Outcome Measure Data

Analysis Population Description

Day 10 data was not gathered from participants per protocol, but it was available for historical controls.

Arm/Group Title	Colchicine Per Protocol	Historical Controls
Arm/Group Description	All patients entered the intended protocol where Colchicine was empirically given 0.6mg once daily to postoperative Fontan patients starting on postoperative day 2 and ending 1 day after chest tubes were removed or for a maximum of 4 weeks. These participants completed the protocol.	Historical Controls were post-operative Fontan patients who underwent their operation at the University of Michigan. They were part of a prospective observational study that was published in 2019 which included the chest tube drainage sample collection similar to that done with the Colchicine cohort in this trial.
Measure Participants	5	25
IL-8 Day 1	60925.80	83263.45
IL-8 Day 2	22178.00	50734.56
IL-8 Day 3	26837.20	36175.15
IL-8 Day 4	50895.36	52203.825
IL-8 Day 7	8684.57	64695.5
IL-8 Day 10	140165.900
IL-10 Day 1	5286.55	14474.4
IL-10 Day 2	2788.440	5341.80
IL-10 Day 3	586.59	1192.29
IL-10 Day 4	448.06	1462.22
IL-10 Day 7	132.755	885.04
IL-10 Day 10	417.80
TNF Alpha Day 1	6552.70	8080.38
TNF Alpha Day 2	6220.50	4761.36
TNF Alpha Day 3	3791.84	3495.45
TNF Alpha Day 4	2517.90	3411.555
TNF Alpha Day 7	694.575	3320.97
TNF Alpha Day 10	2361.60
MIP-Beta Day 1	4949.89	11527.80
MIP-Beta Day 2	3066.80	8822.96
MIP-Beta Day 3	4031.04	6594.00
MIP-Beta Day 4	2730.50	7375.96
MIP-Beta Day 7	247.775	5986.40
MIP-Beta Day 10	8957.13

5. Secondary Outcome

Title	Duration of Pleural Drainage as Measured in Postoperative Fontan Patients Treated Empirically With Colchicine
Description	Duration is measured in days, from date of Fontan surgery to chest tube drainage discontinuation.
Time Frame	Date of chest tube drainage discontinuation, approximately 11 days after surgery

Outcome Measure Data

Analysis Population Description

Intention to Treat compared to colchicine per protocol

Arm/Group Title	Colchicine Intention to Treat	Colchicine Per Protocol
Arm/Group Description	All patients entered the intended protocol where Colchicine was empirically given 0.6mg once daily to postoperative Fontan patients starting on postoperative day 2 and ending 1 day after chest tubes were removed or for a maximum of 4 weeks. This group were all of those who began the protocol, whether they completed it or not.	All patients entered the intended protocol where Colchicine was empirically given 0.6mg once daily to postoperative Fontan patients starting on postoperative day 2 and ending 1 day after chest tubes were removed or for a maximum of 4 weeks. These patients completed the entire protocol.
Measure Participants	9	5
Median (Inter-Quartile Range) [days]	7.5	6

6. Secondary Outcome

Title	Difference of Duration of Pleural Drainage of Two Groups, in Empiric Treatment With Colchicine Compared to a Cohort of Fontan Patients Not Treated With Colchicine
Description	Duration is measured in days, from date of Fontan surgery to chest tube drainage discontinuation
Time Frame	Date of chest tube drainage discontinuation, approximately 11 days after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colchicine Per Protocol	Colchinine Intention to Treat	Historical Controls
Arm/Group Description	All patients entered the intended protocol where Colchicine was empirically given 0.6mg once daily to postoperative Fontan patients starting on postoperative day 2 and ending 1 day after chest tubes were removed or for a maximum of 4 weeks. These participants completed the protocol.	All patients entered the intended protocol where Colchicine was empirically given 0.6mg once daily to postoperative Fontan patients starting on postoperative day 2 and ending 1 day after chest tubes were removed or for a maximum of 4 weeks. These participants were in the trial at least initially, but not all completed the protocol.	Historical Controls were post-operative Fontan patients who underwent their operation at the University of Michigan. They were part of a prospective observational study that was published in 2019 which included the chest tube drainage sample collection similar to that done with the Colchicine cohort in this trial.
Measure Participants	5	9	25
Median (Inter-Quartile Range) [days]	6	7.5	10

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colchicine Per Protocol, Historical Controls
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Historical Controls, Historical Controls
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.17
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

7. Secondary Outcome

Title	Hospital Length of Stay as Measured in Postoperative Fontan Patients Treated Empirically With Colchicine
Description	Measured in days, from date of Fontan surgery to chest tube drainage discontinuation
Time Frame	Hospital discharge at study completion, approximately 2 weeks after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colchicine Intention to Treat	Colchicine Per Protocol
Arm/Group Description	All patients entered the intended protocol where Colchicine was empirically given 0.6mg once daily to postoperative Fontan patients starting on postoperative day 2 and ending 1 day after chest tubes were removed or for a maximum of 4 weeks. These patients were all those assigned to the protocol whether they completed it or not.	All patients entered the intended protocol where Colchicine was empirically given 0.6mg once daily to postoperative Fontan patients starting on postoperative day 2 and ending 1 day after chest tubes were removed or for a maximum of 4 weeks. These patients completed the entire protocol.
Measure Participants	9	5
Median (Inter-Quartile Range) [days]	9	7

8. Secondary Outcome

Title	Difference in Hospital Length of Stay
Description	Measured in days compared to historical controls
Time Frame	Hospital discharge at study completion, approximately 2 weeks after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colchicine Per Protocol	Colchicine Intention to Treat	Historical Controls
Arm/Group Description	All patients entered the intended protocol where Colchicine was empirically given 0.6mg once daily to postoperative Fontan patients starting on postoperative day 2 and ending 1 day after chest tubes were removed or for a maximum of 4 weeks. These patients completed the entire protocol.	All patients entered the intended protocol where Colchicine was empirically given 0.6mg once daily to postoperative Fontan patients starting on postoperative day 2 and ending 1 day after chest tubes were removed or for a maximum of 4 weeks. All of these participants began the protocol, but not all these participants completed the protocol.	Historical Controls were post-operative Fontan patients who underwent their operation at the University of Michigan. They were part of a prospective observational study that was published in 2019 which included the chest tube drainage sample collection similar to that done with the Colchicine cohort in this trial.
Measure Participants	5	9	25
Median (Inter-Quartile Range) [days]	7	9	11

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colchicine Per Protocol, Historical Controls
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Historical Controls, Historical Controls
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.13
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	from initiation of study through 5-14 days after last dose of colchicine (generally 12 -21 days)
Adverse Event Reporting Description	As noted earlier under Participant Flow, historical controls were not considered enrolled in this trial. Further, the historical control information comes from an observational study in which Adverse Events were not collected. Thus, historical control data is not presented.
Arm/Group Title	Colchicine
Arm/Group Description	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. Colchicine: Colchicine is an alkaloid approved in 1961 for the use in Familial Mediterranean Fever in adults and children 4 years of age or older. 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.
All Cause Mortality
	Colchicine
	Affected / at Risk (%)	# Events
Total	0/9 (0%)
Serious Adverse Events
	Colchicine
	Affected / at Risk (%)	# Events
Total	0/9 (0%)
Other (Not Including Serious) Adverse Events
	Colchicine
	Affected / at Risk (%)	# Events
Total	9/9 (100%)
Gastrointestinal disorders
nausea	5/9 (55.6%)
diarrhea	1/9 (11.1%)
vomiting	5/9 (55.6%)
loose stool	1/9 (11.1%)
abdominal pain	1/9 (11.1%)
Hepatobiliary disorders
hepatic dysfunction	1/9 (11.1%)
Renal and urinary disorders
increase in creatinine	1/9 (11.1%)
Respiratory, thoracic and mediastinal disorders
pleural effusion	1/9 (11.1%)
Skin and subcutaneous tissue disorders
rash	1/9 (11.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.