Kidney FailurePhase 3NCT04258423
Everolimus Plus Mycophenolic Acid for Kidney Preservation in Liver Transplant Recipients With Impaired Kidney Function
A Phase 3 study testing Tacrolimus and Everolimus in people with Kidney Failure, run by Indiana University at 1 site in United States.
Trial summary
Tacrolimus is the standard immunosuppressive drug used to prevent organ rejection post liver transplant. One side effect of Tacrolimus is nephrotoxicity. Everolimus does not have the nephrotoxicity side effects of Tacrolimus. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Kidney Failure
- What is being tested?
- Tacrolimus and Everolimus
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 4 participants
- Where
- 1 siteUnited States
- Study dates
- 19 Dec 2019to 27 Jun 2020
- Phase
- Phase 3
- 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Liver transplant recipients ≥ 18 years old
- Baseline renal dysfunction (GFR ≤ 60 mL/min)
- Rabbit anti-thymocyte globulin (rATG) induction (cumulative dose 3 - 5 mg/kg)
- Indication for transplant: ethanol, hepatitis C, or nonalcoholic steatohepatitis
Who cannot join
- Increased risk of rejection: autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, positive crossmatch, retransplantation
- Incompletely healed incision or other wound healing issues at time of randomization
- Multiple or previous organ transplantation
- Severe, uncontrolled hypercholesterolemia (> 9mmol/L) or hypertriglyceridemia (>8.5 mmol/L) in the 6 mo prior to transplantation
- Insurance company unwilling to pay for the cost of the everolimus
- Pregnant women
- Unable to provide informed consent
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Preservation of Renal Function After Liver Transplant for Patients With Pre-existing Chronic Kidney Disease or Peri-operative Acute Kidney Injury Using Everolimus Plus Mycophenolate Mofetil Immunosuppression Regimen
Tacrolimus is the standard immunosuppressive drug used to prevent organ rejection post liver transplant. One side effect of Tacrolimus is nephrotoxicity. Everolimus does not have the nephrotoxicity side effects of Tacrolimus. Replacement of Tacrolimus by Everolimus may have a reduced incidence of renal dysfunction in liver transplant patients who already have chronic kidney disease or peri-operative acute kidney injury. Liver transplant patients receive potent induction immunosuppression in the form of rabbit anti thymocyte globulin. Investigators believe that in conjunction with this induction regimen, patients can be maintained on Everolimus monotherapy without the risk of rejection. Additionally, Everolimus is known to induce tolerance in transplant recipients. Tolerant patients do not require immunosuppression to accept transplant organs. Tacrolimus is a widely used in liver transplant recipients for immunosuppression, however it is associated with nephrotoxicity. Everolimus, on the other hand lacks nephrotoxicity. Whether replacement of tacrolimus by Everolimus preserves kidney function in patients with pre-existing chronic kidney disease or acute kidney injury is not well established. Also, the efficacy and safety of reduced-dose Everolimus with or without Mycophenolate Mofetil in prevention of rejection is unknown.
Primary Aim Assess the effect of Everolimus with or without Mycophenolate Mofetil versus Tacrolimus plus Mycophenolate Mofetil therapy on renal function measured by Glomerular Filtration Rate (GFR). Secondary Aims
Read more
Compare the efficacy of Everolimus plus Mycophenolate Mofetil versus Tacrolimus plus Mycophenolate Mofetil therapy as measured by the following:
- Biopsy-confirmed acute rejection
- Hyperlipidemia
- Proteinuria
- % regulatory T-cells in circulation
- NODAT [New Onset Diabetes mellitus After Transplant], hypertension and malignancy
- Tolerance measured by gene profiling at year 1, 2 and 3
Read the detailed description
Following transplant, prior to the one month post transplant visit, subjects will be approached either in the transplant unit in the hospital or at the transplant clinic in the hospital for study participation. Following enrollment, subjects will be randomized at one month post transplant to reduced dose Tacrolimus plus Mycophenolate Mofetil immunosuppression (control group) or to Everolimus plus Mycophenolate Mofetil (study group) maintenance immunosuppression.
After liver transplant, all patients will receive the standard induction regimen and Tacrolimus monotherapy.
INDUCTION:
Rabbit anti-thymocyte globulin (rATG) 1.5 mg/kg of actual body weight rounded to nearest 25 mg and capped at 150 mg for up to three doses given IV on post-operative day (POD) 1, 3, and 5. Some patients may receive only one dose if considered too frail to need all three doses.
30 minutes prior to infusion, pre-medicate with the following: Daily steroid dose Acetaminophen (Tylenol®) 650 mg PO or per NG x 1 dose B - Lay Summary \& Research Design Diphenhydramine (Benadryl®) 25 mg IV push x 1 dose
Steroids:
Methylprednisolone (Solu-Medrol®) 250 mg IV push x 1 dose on POD 1 (given 30 minutes prior to rATG) and 125 mg IV push x 1 dose on POD 3.
Maintenance:
Low dose Tacrolimus (FK / Prograf®) (titrated to a goal trough of 6 ± 1 ng/mL) plus Mycophenolate Mofetil 500 mg BID.
RANDOMIZATION:
On POD 30, patients meeting study criteria will be randomized to either the study arm or control arm. Patients randomized to the study arm will be converted to Everolimus (target trough levels 4-8 ng/mL) plus Mycophenolate Mofetil 500 mg BID therapy. The control arm will be maintained on the low dose Tacrolimus plus Mycophenolate Mofetil therapy.
At 3 months, patients with GFR <=60 will proceed to reduced dose Everolimus (target trough levels 3-6 ng/mL) plus Mycophenolate Mofetil 500 mg BID therapy. Patients with GFR >60 will proceed to Everolimus monotherapy (target trough levels 4-8 ng/mL).
Complete blood counts, liver function panels, and drug levels will be monitored per Standard of Care [SOC]: initially twice per week for first month, once per week for next two months, once every other week for next three weeks, and then once monthly. Ultrasound, ERCP, biopsy as needed by clinical situation as SOC.
- Conditions
- Kidney Failure
- Being tested
- Tacrolimus, Everolimus
- Medical subject headings
- Renal Insufficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TacrolimusDrug
Also called Prograf
Low dose Tacrolimus
EverolimusDrug
Also called Zortress
Everolimus
| Study group | Role | What they receive |
|---|---|---|
| Control Arm | Active comparator | Tacrolimus as maintenance immunosuppression Receives: Drug: Tacrolimus |
| Study Arm | Experimental | Everolimus as maintenance immunosuppression Receives: Drug: Everolimus |
What is being measured
The primary outcome is the main question the study is designed to answer.
Glomerular Filtration Rate in Patients Treated With Tacrolimus
Glomerular Filtration Rate
Measured: 36 months post-transplant
Glomerular Filtration Rate in Patients Treated With Everolimus
Glomerular Filtration Rate
Measured: 36 months post-transplant
Number of Patients Who Experience Transplant Rejection
Biopsy
Measured: 36 months post-transplant
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Feb 2020
- Study start19 Dec 2019
- Primary completion27 Jun 2020
- Study completion27 Jun 2020
Why it stopped: Study was larger than expected and became a burden to faculty and staff resources.
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.
- Other trials for Kidney FailureStudies of the same condition, open and under way.
- More trials run by Indiana UniversityThe 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 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Tacrolimus as maintenance immunosuppression, then randomized to Everolimus plus Mycophenolate Mofetil, discontinuing Tacrolimus once Everolimus level within goal range OR randomized to continued maintenance with Tacrolimus plus Mycophenolate Mofetil.
- Masking
- None (open label)
- Enrolment
- 4 participants (actual)
Sponsor and investigators
- Lead sponsor
- Indiana University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Chandrashekhar Kubal, Indiana University
- Investigators
- Chandrashekhar Kubal, MD, Principal investigator, Indiana University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04258423
- Sponsor's protocol ID
- 1807596072
- Status last verified
- Apr 2023
- First submitted
- 31 Jan 2020
- Last updated
- 24 May 2023
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 24 May 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Preservation of Renal Function After Liver Transplant for Patients With Pre-existing Chronic Kidney Disease or Peri-operative Acute Kidney Injury Using Everolimus Plus Mycophenolate Mofetil Immunosuppression Regimen
- ClinicalTrials.gov ID
- NCT04258423
- Acronym / sponsor ID
- 1807596072
- Conditions
- Kidney Failure
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Study was larger than expected and became a burden to faculty and staff resources.
- Enrolment
- 4 participants (actual)
- Lead sponsor
- Indiana UniversityUniversity, hospital or other
- Study start
- 19 Dec 2019 (actual)
- Primary completion
- 27 Jun 2020 (actual)
- Study completion
- 27 Jun 2020 (actual)
- First posted
- 6 Feb 2020 (actual)
- Results
- Posted 24 May 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Tacrolimus is the standard immunosuppressive drug used to prevent organ rejection post liver transplant. One side effect of Tacrolimus is nephrotoxicity. Everolimus does not have the nephrotoxicity side effects of Tacrolimus. Replacement of Tacrolimus by Everolimus may have a reduced incidence of renal dysfunction in liver transplant patients who already have chronic kidney disease or peri-operative acute kidney injury. Liver transplant patients receive potent induction immunosuppression in the form of rabbit anti thymocyte globulin. Investigators believe that in conjunction with this induction regimen, patients can be maintained on Everolimus monotherapy without the risk of rejection. Additionally, Everolimus is known to induce tolerance in transplant recipients. Tolerant patients do not require immunosuppression to accept transplant organs. Tacrolimus is a widely used in liver transplant recipients for immunosuppression, however it is associated with nephrotoxicity. Everolimus, on the other hand lacks nephrotoxicity. Whether replacement of tacrolimus by Everolimus preserves kidney function in patients with pre-existing chronic kidney disease or acute kidney injury is not well established. Also, the efficacy and safety of reduced-dose Everolimus with or without Mycophenolate Mofetil in prevention of rejection is unknown.
Primary Aim Assess the effect of Everolimus with or without Mycophenolate Mofetil versus Tacrolimus plus Mycophenolate Mofetil therapy on renal function measured by Glomerular Filtration Rate (GFR). Secondary Aims
Compare the efficacy of Everolimus plus Mycophenolate Mofetil versus Tacrolimus plus Mycophenolate Mofetil therapy as measured by the following:
- Biopsy-confirmed acute rejection
- Hyperlipidemia
- Proteinuria
- % regulatory T-cells in circulation
- NODAT [New Onset Diabetes mellitus After Transplant], hypertension and malignancy
- Tolerance measured by gene profiling at year 1, 2 and 3
Detailed description
Following transplant, prior to the one month post transplant visit, subjects will be approached either in the transplant unit in the hospital or at the transplant clinic in the hospital for study participation. Following enrollment, subjects will be randomized at one month post transplant to reduced dose Tacrolimus plus Mycophenolate Mofetil immunosuppression (control group) or to Everolimus plus Mycophenolate Mofetil (study group) maintenance immunosuppression.
After liver transplant, all patients will receive the standard induction regimen and Tacrolimus monotherapy.
INDUCTION:
Rabbit anti-thymocyte globulin (rATG) 1.5 mg/kg of actual body weight rounded to nearest 25 mg and capped at 150 mg for up to three doses given IV on post-operative day (POD) 1, 3, and 5. Some patients may receive only one dose if considered too frail to need all three doses.
30 minutes prior to infusion, pre-medicate with the following: Daily steroid dose Acetaminophen (Tylenol®) 650 mg PO or per NG x 1 dose B - Lay Summary \& Research Design Diphenhydramine (Benadryl®) 25 mg IV push x 1 dose
Steroids:
Methylprednisolone (Solu-Medrol®) 250 mg IV push x 1 dose on POD 1 (given 30 minutes prior to rATG) and 125 mg IV push x 1 dose on POD 3.
Maintenance:
Low dose Tacrolimus (FK / Prograf®) (titrated to a goal trough of 6 ± 1 ng/mL) plus Mycophenolate Mofetil 500 mg BID.
RANDOMIZATION:
On POD 30, patients meeting study criteria will be randomized to either the study arm or control arm. Patients randomized to the study arm will be converted to Everolimus (target trough levels 4-8 ng/mL) plus Mycophenolate Mofetil 500 mg BID therapy. The control arm will be maintained on the low dose Tacrolimus plus Mycophenolate Mofetil therapy.
At 3 months, patients with GFR <=60 will proceed to reduced dose Everolimus (target trough levels 3-6 ng/mL) plus Mycophenolate Mofetil 500 mg BID therapy. Patients with GFR >60 will proceed to Everolimus monotherapy (target trough levels 4-8 ng/mL).
Complete blood counts, liver function panels, and drug levels will be monitored per Standard of Care [SOC]: initially twice per week for first month, once per week for next two months, once every other week for next three weeks, and then once monthly. Ultrasound, ERCP, biopsy as needed by clinical situation as SOC.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Tacrolimus as maintenance immunosuppression, then randomized to Everolimus plus Mycophenolate Mofetil, discontinuing Tacrolimus once Everolimus level within goal range OR randomized to continued maintenance with Tacrolimus plus Mycophenolate Mofetil.
| Arm | Type | Receives |
|---|---|---|
| Control Arm | Active comparator | Drug: TacrolimusTacrolimus as maintenance immunosuppression |
| Study Arm | Experimental | Drug: EverolimusEverolimus as maintenance immunosuppression |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Liver transplant recipients ≥ 18 years old
- Baseline renal dysfunction (GFR ≤ 60 mL/min)
- Rabbit anti-thymocyte globulin (rATG) induction (cumulative dose 3 - 5 mg/kg)
- Indication for transplant: ethanol, hepatitis C, or nonalcoholic steatohepatitis
Key exclusion criteria (7 listed)
- Increased risk of rejection: autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, positive crossmatch, retransplantation
- Incompletely healed incision or other wound healing issues at time of randomization
- Multiple or previous organ transplantation
- Severe, uncontrolled hypercholesterolemia (> 9mmol/L) or hypertriglyceridemia (>8.5 mmol/L) in the 6 mo prior to transplantation
- Insurance company unwilling to pay for the cost of the everolimus
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 |
|---|---|---|
| TacrolimusAlso: PrografLow dose Tacrolimus | Drug | Control Arm |
| EverolimusAlso: ZortressEverolimus | Drug | Study Arm |
Primary outcome
Glomerular Filtration Rate in Patients Treated With Tacrolimus
Time frame: 36 months post-transplant
Glomerular Filtration Rate
Glomerular Filtration Rate in Patients Treated With Everolimus
Time frame: 36 months post-transplant
Glomerular Filtration Rate
Number of Patients Who Experience Transplant Rejection
Time frame: 36 months post-transplant
Biopsy
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 May 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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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.
Chandrashekhar Kubal, MD principal investigator
Indiana University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Tacrolimus and Everolimus in people with Kidney Failure, run by Indiana University at 1 site 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 4 inclusion and 7 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: stopped early, as of the sponsor's last update on 24 May 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site 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. 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 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
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 24 May 2023). 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?
Glomerular Filtration Rate in Patients Treated With Tacrolimus (time frame: 36 months post-transplant). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 24 May 2023.