A Randomized Controlled Clinical Trial of Thymoglobulin® After Liver Transplantation

A Randomized Controlled Clinical Trial of Thymoglobulin® and Extended Delay of Calcineurin Inhibitor Therapy for Renal Protection After Liver Transplantation. A Multi-Center Study

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.

Study Overview

• Status: Completed
• Conditions: Liver Failure
• Intervention / Treatment: Drug: Thymoglobulin; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 110
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Weston, Florida, United States, 33331
      • Cleveland Clinic Florida
  • Ohio
    • Cincinnati, Ohio, United States
      • University of Cincinnati College of Medicine
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic (Main Campus)
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Incidence of Acute Kidney Injury (AKI) as Assessed by Change in Serum Creatinine From Baseline to 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.	30 days post-transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing Acute Cellular Rejection	The number of participants experiencing acute cellular rejection, as determined by biopsy.	30 days post OLT
Graft Survival	Number of participants who did not require retransplantation	6 months post OLT

Collaborators and Investigators

• Sponsor: The Cleveland Clinic
• Investigators: Principal Investigator: Bijan Eghtesad, The Cleveland Clinic

Publications and helpful links

General Publications

• Nair A, Coromina Hernandez L, Shah S, Zervos X, Zimmerman M, Sasaki K, Diago T, Hashimoto K, Fujiki M, Aucejo F, Bollinger J, Kaiser TL, Miller CM, Quintini C, Fung JJ, Eghtesad B. Induction Therapy With Antithymocyte Globulin and Delayed Calcineurin Inhibitor Initiation for Renal Protection in Liver Transplantation: A Multicenter Randomized Controlled Phase II-B Trial. Transplantation. 2022 May 1;106(5):997-1003. doi: 10.1097/TP.0000000000003904. Epub 2021 Jul 27.

Study record dates

Study Major Dates

• Study Start: December 1, 2015
• Primary Completion (Actual): June 26, 2018
• Study Completion (Actual): January 3, 2020

Study Registration Dates

• First Submitted: September 1, 2015
• First Submitted That Met QC Criteria: September 4, 2015
• First Posted (Estimate): September 9, 2015

Study Record Updates

• Last Update Posted (Actual): May 6, 2021
• Last Update Submitted That Met QC Criteria: May 5, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Hepatic Insufficiency; Liver Diseases; Liver Failure; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Thymoglobulin; Antilymphocyte Serum
• Other Study ID Numbers: 15-943

Drug and device information, study documents

• 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