Liver FailurePhase 2NCT02544113
A Randomized Controlled Clinical Trial of Thymoglobulin® After Liver Transplantation
A Phase 2 study testing Thymoglobulin in people with Liver Failure, run by The Cleveland Clinic at 4 sites in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Liver Failure
- What is being tested?
- Thymoglobulin
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 110 participants
- Where
- 4 sitesUnited States
- Study dates
- Dec 2015to 3 Jan 2020
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 12Show fewer
- 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.
Trial locations and contacts
4 sites in 1 country.
United States4 sites
University of Cincinnati College of Medicine
Cincinnati, Ohio
Cleveland Clinic (Main Campus)
Cleveland, Ohio, 44195
Medical College of Wisconsin
Milwaukee, Wisconsin, 53226
Cleveland Clinic Florida
Weston, Florida, 33331
About this study
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
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).
Read more
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.
Read the 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.
- Conditions
- Liver Failure
- Being tested
- Thymoglobulin, Placebo
- Medical subject headings
- Liver Failure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ThymoglobulinDrug
Also called Anti-thymocyte Globulin
Treatment with thymoglobulin and delayed CNI post OLT
PlaceboDrug
Normal transplant immunosuppression
| Study group | Role | What they receive |
|---|---|---|
| Thymo | Experimental | 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. Receives: Drug: Thymoglobulin |
| Control | Placebo comparator | 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. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 30 days post-transplant
Secondary outcomes (2)
Number of Participants Experiencing Acute Cellular Rejection
The number of participants experiencing acute cellular rejection, as determined by biopsy.
Measured: 30 days post OLT
Graft Survival
Number of participants who did not require retransplantation
Measured: 6 months post OLT
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Sep 2015 (estimated)
- Study startDec 2015
- Primary completion26 Jun 2018
- Study completion3 Jan 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Liver FailureStudies of the same condition, open and under way.
- More trials run by The Cleveland ClinicThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 110 participants (actual)
Sponsor and investigators
- Lead sponsor
- The Cleveland Clinic
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Bijan Eghtesad, MD, The Cleveland Clinic
- Investigators
- Bijan Eghtesad, Principal investigator, The Cleveland Clinic
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02544113
- Sponsor's protocol ID
- 15-943
- Status last verified
- May 2021
- First submitted
- 1 Sep 2015
- Last updated
- 6 May 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
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.
PubMed 34319926
Study at a glance
From the registry record, last updated by the sponsor on 6 May 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02544113
- Acronym / sponsor ID
- 15-943
- Conditions
- Liver Failure
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 110 participants (actual)
- Lead sponsor
- The Cleveland ClinicUniversity, hospital or other
- Study start
- Dec 2015
- Primary completion
- 26 Jun 2018 (actual)
- Study completion
- 3 Jan 2020 (actual)
- First posted
- 9 Sep 2015 (estimated)
- Results
- Posted 6 May 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Thymo | Experimental | Drug: ThymoglobulinSubjects 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. |
| Control | Placebo comparator | Drug: PlaceboSubjects 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. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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)
Key exclusion criteria (12 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ThymoglobulinAlso: Anti-thymocyte GlobulinTreatment with thymoglobulin and delayed CNI post OLT | Drug | Thymo |
| PlaceboNormal transplant immunosuppression | Drug | Control |
Primary outcome
The Incidence of Acute Kidney Injury (AKI) as Assessed by Change in Serum Creatinine From Baseline to 30 Days Post-transplant
Time frame: 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.
2 secondary outcomes
Number of Participants Experiencing Acute Cellular Rejection
Time frame: 30 days post OLT
Graft Survival
Time frame: 6 months post OLT
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 May 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 34319926Nair 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.
Related trials for Liver Failure
Not yet recruiting
Double Plasma Separation and Adsorption in Acute-on-Chronic Liver Failure (DPMAS-ACLF Trial)
Acute-on-Chronic Liver Failure (ACLF)
Not yet recruiting
Vitamin C for Acute Kidney Injury in ACLF With Septic Shock: A Randomized Controlled Trial
Acute-on-Chronic Liver Failure (ACLF)
RecruitingObservational study
Longitudinal Study of Ultra-rare Inherited Metabolic and Degenerative Neurological Diseases.
Inherited Disease, Rare Diseases
Active, not recruiting
LiverPAL: A Trial of Inpatient Palliative Care for Patients With Advanced Liver Disease
Liver Disease Chronic, End Stage Liver DIsease
RecruitingObservational study
Establishing a Reference Framework for Outcomes After Machine-Preserved Liver Transplantation in Europe
End-stage Liver Disease (ESLD), Acute Liver Failure
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Bijan Eghtesad principal investigator
The Cleveland Clinic
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Thymoglobulin in people with Liver Failure, run by The Cleveland Clinic at 4 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 May 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 6 May 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The Incidence of Acute Kidney Injury (AKI) as Assessed by Change in Serum Creatinine From Baseline to 30 Days Post-transplant (time frame: 30 days post-transplant). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02544113, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 May 2021.