A Randomized Controlled Clinical Trial of Thymoglobulin® After Liver Transplantation

• Sponsor: The Cleveland Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT02544113
• Collaborator: (none)
• Enrollment: 110
• Locations: 4
• Arms: 2
• Duration (Months): 49.1
• Patients Per Site: 27.5
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

This is a 24-month, Phase II, multi-center, two-arm, randomized controlled study of adult patients receiving a single organ liver transplant from a deceased donor; the purpose being to determine the efficacy of Thymoglobulin® induction and delayed initiation of CNI in the long-term preservation of renal function after liver transplantation. This study is based on the outcomes of an earlier phase 1 pilot study which was performed at the Cleveland Clinic.

This study will be conducted at 3 centers, with 110 subjects randomized 1:1 into two groups:

Group 1 will receive Thymoglobulin® induction, (4.5 mg/Kg, in 3 doses of 1.5 mg/Kg/dose) with delayed initiation of CNI to begin on Day 10 post LT. Group 2 will receive early CNI initiation (to be started no later than Day 2 post LT), and no Thymoglobulin® induction (or any other antibody).

All subjects will also receive a maintenance immunosuppressive regimen consisting of corticosteroids and mycophenolate mofetil (MMF) according to standard of practice in orthotopic liver transplantation (OLT).

Subjects will be consented pre-transplant. Participation may last up to 12 months post OLT. There are 15 study-related visits which will be completed during standard of care (SOC) visits.

Condition or Disease	Intervention/Treatment	Phase
Liver Failure	Drug: Thymoglobulin; Drug: Placebo	Phase 2

Detailed Description

Functional recovery of renal function from acute renal failure occurs in 75% of patients at approximately 14 days after onset of the disease. In liver transplantation, intraoperative hemodynamic insults typically lead to acute renal failure which may be further worsened by exposure to CNI therapy in the early postoperative period. In practice, patients who demonstrate early evidence of acute renal failure often have their CNI therapy delayed for 4-5 days. This duration of CNI delay is too short to have any salutary effect on the course or severity of acute kidney injury as less than 20% of patients experience any functional recovery by day 5.

Thymoglobulin® (Sanofi, Cambridge, MA) is a polyclonal immunosuppressive agent that is derived from rabbits immunized with pediatric thymocytes. It contains antibodies to a wide variety of T-cell antigens and major histocompatibility complex (MHC) antigens and is approved for the treatment of kidney rejection by the FDA. Thymoglobulin® has been shown to be a safe and efficacious induction therapy that permits delayed exposure to CNI therapy while preventing the occurrence of acute rejection in kidney transplantation. The investigators hypothesize that any perioperative insult leading to AKI in OLT recipients is unlikely to be beneficially impacted by a short delay of CNI introduction. Further hypothesized is that avoidance of CNI for 10 days will have a beneficial effect on the course and severity of perioperative AKI. Since perioperative AKI is a potent risk factor for chronic kidney disease (CKD) in the late post-transplant period, also hypothesized is that minimizing the risk and severity of AKI with prolonged delayed exposure to CNI will have a beneficial effect on renal function late after liver transplantation.

Study Design

• Study Type: Interventional
• Actual Enrollment: 110 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Controlled Clinical Trial of Thymoglobulin® and Extended Delay of Calcineurin Inhibitor Therapy for Renal Protection After Liver Transplantation. A Multi-Center Study
• Study Start Date: Dec 1, 2015
• Actual Primary Completion Date: Jun 26, 2018
• Actual Study Completion Date: Jan 3, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Thymo Subjects randomized to the (Delay CNI) group will be treated with Thymoglobulin® (total dose of 4.5 mg/kg) administered in three doses; (each dose being 1.5 mg/kg - administered Day 0 [after transplant], Day 2, and Day 4 post transplant), along with CNI delay for 10 days. CNI will be initiated on postoperative (post-transplant) Day 10. Subjects will also receive a maintenance immunosuppression regimen of corticosteroids and MMF in accordance with the standard practice at each clinical center.	Drug: Thymoglobulin; Treatment with thymoglobulin and delayed CNI post OLT; Other Names: Anti-thymocyte Globulin
Placebo Comparator: Control Subjects randomized to the (Early CNI) group (Control group) will receive no antibody therapy for induction and will start CNI therapy on postoperative (post-transplant) Day 2. Subjects will also receive a maintenance immunosuppression regimen of corticosteroids and MMF in accordance with the standard practice at each clinical center.	Drug: Placebo; Normal transplant immunosuppression

Outcome Measures

Primary Outcome Measures

1. The Incidence of Acute Kidney Injury (AKI) as Assessed by Change in Serum Creatinine From Baseline to 30 Days Post-transplant [30 days post-transplant]

   Change in serum creatinine from baseline to 30 days post-transplant. Higher values are associated with worse outcomes, and values greater than 0.3 mg/dL are suggestive of acute kidney injury.

Secondary Outcome Measures

1. Number of Participants Experiencing Acute Cellular Rejection [30 days post OLT]

   The number of participants experiencing acute cellular rejection, as determined by biopsy.

2. Graft Survival [6 months post OLT]

   Number of participants who did not require retransplantation

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients undergoing deceased donor solitary liver transplantation

• Age 18-75 years at the time of transplantation

• Willingness and ability to comply with the study procedures

• Signed informed consent form

• For patients with Hepatocellular carcinoma as indication for OLT, (must be within the Milan Criteria)

• Hepatitis C, positive or negative, patients

Exclusion Criteria:

• Prior kidney transplantation

• Congenital or iatrogenic absence of one kidney

• Subjects on renal replacement therapy at the time of OLT

• MELD score >34

• HIV positive patient

• Patient with current severe systemic infection

• History of bacterial peritonitis within 30 days prior to OLT

• Active infection or recent infection within 30 days prior to OLT

• Use of a calcineurin inhibitor continuously for more than 90 days within the past 6 months

• History of hypersensitivity to Thymoglobulin®, rabbits or tacrolimus

• Pregnant and/or nursing (lactating) females.

• Women of childbearing age who are unwilling to use effective contraception during the duration of the study, and for 30 days after study participation and/or last dose of Study Drug.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cleveland Clinic Florida	Weston	Florida	United States	33331
2	University of Cincinnati College of Medicine	Cincinnati	Ohio	United States
3	Cleveland Clinic (Main Campus)	Cleveland	Ohio	United States	44195
4	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• The Cleveland Clinic

Investigators

• Principal Investigator: Bijan Eghtesad, The Cleveland Clinic

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 27, 2017

More Information

Publications

None provided.

• Responsible Party: Bijan Eghtesad, MD, Staff Surgeon, The Cleveland Clinic
• ClinicalTrials.gov Identifier: NCT02544113
• Other Study ID Numbers: 15-943
• First Posted: Sep 9, 2015
• Last Update Posted: May 6, 2021
• Last Verified: May 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Liver Failure; Thymoglobulin; Antilymphocyte Serum

Study Results

Participant Flow

Arm/Group Title	Thymo	Control
Arm/Group Description	Subjects randomized to the (Delay CNI) group will be treated with Thymoglobulin® (total dose of 4.5 mg/kg) administered in three doses; (each dose being 1.5 mg/kg - administered Day 0 [after transplant], Day 2, and Day 4 post transplant), along with CNI delay for 10 days. CNI will be initiated on postoperative (post-transplant) Day 10. Subjects will also receive a maintenance immunosuppression regimen of corticosteroids and MMF in accordance with the standard practice at each clinical center. Thymoglobulin: Treatment with thymoglobulin and delayed CNI post OLT	Subjects randomized to the (Early CNI) group (Control group) will receive no antibody therapy for induction and will start CNI therapy on postoperative (post-transplant) Day 2. Subjects will also receive a maintenance immunosuppression regimen of corticosteroids and MMF in accordance with the standard practice at each clinical center. Placebo: Normal transplant immunosuppression
Period Title: Overall Study
STARTED	55	55
COMPLETED	52	51
NOT COMPLETED	3	4

Baseline Characteristics

Arm/Group Title	Thymo	Control	Total
Arm/Group Description	Subjects randomized to the (Delay CNI) group will be treated with Thymoglobulin® (total dose of 4.5 mg/kg) administered in three doses; (each dose being 1.5 mg/kg - administered Day 0 [after transplant], Day 2, and Day 4 post transplant), along with CNI delay for 10 days. CNI will be initiated on postoperative (post-transplant) Day 10. Subjects will also receive a maintenance immunosuppression regimen of corticosteroids and MMF in accordance with the standard practice at each clinical center. Thymoglobulin: Treatment with thymoglobulin and delayed CNI post OLT	Subjects randomized to the (Early CNI) group (Control group) will receive no antibody therapy for induction and will start CNI therapy on postoperative (post-transplant) Day 2. Subjects will also receive a maintenance immunosuppression regimen of corticosteroids and MMF in accordance with the standard practice at each clinical center. Placebo: Normal transplant immunosuppression	Total of all reporting groups
Overall Participants	55	55	110
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.1 (12.2)	59.8 (12.1)	58.5 (12.2)
Sex: Female, Male (Count of Participants)
Female	15 27.3%	22 40%	37 33.6%
Male	40 72.7%	33 60%	73 66.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 1.8%	1 1.8%	2 1.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 1.8%	1 1.8%	2 1.8%
White	52 94.5%	49 89.1%	101 91.8%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 1.8%	4 7.3%	5 4.5%

Outcome Measures

1. Primary Outcome

Title	The Incidence of Acute Kidney Injury (AKI) as Assessed by Change in Serum Creatinine From Baseline to 30 Days Post-transplant
Description	Change in serum creatinine from baseline to 30 days post-transplant. Higher values are associated with worse outcomes, and values greater than 0.3 mg/dL are suggestive of acute kidney injury.
Time Frame	30 days post-transplant

Outcome Measure Data

Analysis Population Description

Analysis was performed on a complete-case basis. Outcome measure data was not available for all enrolled subjects.

Arm/Group Title	Thymo	Control
Arm/Group Description	Subjects randomized to the (Delay CNI) group will be treated with Thymoglobulin® (total dose of 4.5 mg/kg) administered in three doses; (each dose being 1.5 mg/kg - administered Day 0 [after transplant], Day 2, and Day 4 post transplant), along with CNI delay for 10 days. CNI will be initiated on postoperative (post-transplant) Day 10. Subjects will also receive a maintenance immunosuppression regimen of corticosteroids and MMF in accordance with the standard practice at each clinical center. Thymoglobulin: Treatment with thymoglobulin and delayed CNI post OLT	Subjects randomized to the (Early CNI) group (Control group) will receive no antibody therapy for induction and will start CNI therapy on postoperative (post-transplant) Day 2. Subjects will also receive a maintenance immunosuppression regimen of corticosteroids and MMF in accordance with the standard practice at each clinical center. Placebo: Normal transplant immunosuppression
Measure Participants	43	52
Mean (Standard Deviation) [mg/dL]	.01 (0.53)	.06 (0.28)

2. Secondary Outcome

Title	Number of Participants Experiencing Acute Cellular Rejection
Description	The number of participants experiencing acute cellular rejection, as determined by biopsy.
Time Frame	30 days post OLT

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Thymo	Control
Arm/Group Description	Subjects randomized to the (Delay CNI) group will be treated with Thymoglobulin® (total dose of 4.5 mg/kg) administered in three doses; (each dose being 1.5 mg/kg - administered Day 0 [after transplant], Day 2, and Day 4 post transplant), along with CNI delay for 10 days. CNI will be initiated on postoperative (post-transplant) Day 10. Subjects will also receive a maintenance immunosuppression regimen of corticosteroids and MMF in accordance with the standard practice at each clinical center. Thymoglobulin: Treatment with thymoglobulin and delayed CNI post OLT	Subjects randomized to the (Early CNI) group (Control group) will receive no antibody therapy for induction and will start CNI therapy on postoperative (post-transplant) Day 2. Subjects will also receive a maintenance immunosuppression regimen of corticosteroids and MMF in accordance with the standard practice at each clinical center. Placebo: Normal transplant immunosuppression
Measure Participants	55	55
Count of Participants [Participants]	9 16.4%	7 12.7%

3. Secondary Outcome

Title	Graft Survival
Description	Number of participants who did not require retransplantation
Time Frame	6 months post OLT

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Thymo	Control
Arm/Group Description	Subjects randomized to the (Delay CNI) group will be treated with Thymoglobulin® (total dose of 4.5 mg/kg) administered in three doses; (each dose being 1.5 mg/kg - administered Day 0 [after transplant], Day 2, and Day 4 post transplant), along with CNI delay for 10 days. CNI will be initiated on postoperative (post-transplant) Day 10. Subjects will also receive a maintenance immunosuppression regimen of corticosteroids and MMF in accordance with the standard practice at each clinical center. Thymoglobulin: Treatment with thymoglobulin and delayed CNI post OLT	Subjects randomized to the (Early CNI) group (Control group) will receive no antibody therapy for induction and will start CNI therapy on postoperative (post-transplant) Day 2. Subjects will also receive a maintenance immunosuppression regimen of corticosteroids and MMF in accordance with the standard practice at each clinical center. Placebo: Normal transplant immunosuppression
Measure Participants	55	55
Count of Participants [Participants]	55 100%	55 100%

Adverse Events

Time Frame	Adverse event data was collected over 12 months
Adverse Event Reporting Description	Participants were assessed for adverse events at regular study visits
Arm/Group Title	Thymo		Control
Arm/Group Description	Subjects randomized to the (Delay CNI) group will be treated with Thymoglobulin® (total dose of 4.5 mg/kg) administered in three doses; (each dose being 1.5 mg/kg - administered Day 0 [after transplant], Day 2, and Day 4 post transplant), along with CNI delay for 10 days. CNI will be initiated on postoperative (post-transplant) Day 10. Subjects will also receive a maintenance immunosuppression regimen of corticosteroids and MMF in accordance with the standard practice at each clinical center. Thymoglobulin: Treatment with thymoglobulin and delayed CNI post OLT		Subjects randomized to the (Early CNI) group (Control group) will receive no antibody therapy for induction and will start CNI therapy on postoperative (post-transplant) Day 2. Subjects will also receive a maintenance immunosuppression regimen of corticosteroids and MMF in accordance with the standard practice at each clinical center. Placebo: Normal transplant immunosuppression
All Cause Mortality
	Thymo		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/55 (5.5%)		4/55 (7.3%)
Serious Adverse Events
	Thymo		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/55 (23.6%)		13/55 (23.6%)
Blood and lymphatic system disorders
Hypertension	1/55 (1.8%)	1	1/55 (1.8%)	1
Hypotension	0/55 (0%)	0	3/55 (5.5%)	3
Gastrointestinal disorders
Bowel Obstruction	1/55 (1.8%)	1	1/55 (1.8%)	1
Hepatobiliary disorders
Hepatic Artery Thrombosis	1/55 (1.8%)	3	1/55 (1.8%)	1
Portal Vein Stenosis	0/55 (0%)	0	1/55 (1.8%)	1
Abnormal Liver Function Tests	5/55 (9.1%)	5	0/55 (0%)	0
Infections and infestations
Infection	8/55 (14.5%)	9	8/55 (14.5%)	11
Nervous system disorders
Seizure	0/55 (0%)	0	1/55 (1.8%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory Insufficiency	0/55 (0%)	0	3/55 (5.5%)	4
Other (Not Including Serious) Adverse Events
	Thymo		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/55 (0%)		0/55 (0%)

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.