Clinical trial NCT02544113: A Randomized Controlled Clinical Trial of Thymoglobulin® After Liver Transplantation
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Liver Failure
Lead sponsor: The Cleveland Clinic
Sponsor class: OTHER
First posted: 2015-09-09
Enrollment: 110
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: The Incidence of Acute Kidney Injury (AKI) as Assessed by Change in Serum Creatinine From Baseline to 30 Days Post-transplant
timeFrame: 30 days post-transplant
Secondary outcomes:
measure: Number of Participants Experiencing Acute Cellular Rejection
timeFrame: 30 days post OLT
measure: Graft Survival
timeFrame: 6 months post OLT
Other outcomes:
Locations:
city: Weston
country: United States
facility: Cleveland Clinic Florida
state: Florida
city: Cincinnati
country: United States
facility: University of Cincinnati College of Medicine
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic (Main Campus)
state: Ohio
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: The Cleveland Clinic
name: Bijan Eghtesad
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.