Kidney FailurePhase 3NCT04063865
Everolimus Monotherapy as Immunosuppression After Liver Transplant
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
- 14 participants
- Where
- 1 siteUnited States
- Study dates
- 9 May 2019to 2 Jul 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
- Normal baseline renal dysfunction (GFR > 60 mL/min)
- Rabbit anti-thymocyte globulin (rATG) induction (cumulative dose 1.5 - 5 mg/kg)
- Indication for transplant: ethanol, hepatitis C, or nonalcoholic steatohepatitis or any combination of these
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 months prior to transplantation
- Insurance company unwilling to pay for the cost of the everolimus or patient does not qualify for the Novartis Patient Assistance Program.
- Pregnant women
- Unable to provide informed consent
Trial locations and contacts
1 site in 1 country.
United States1 site
IU Health University Hospital
Indianapolis, Indiana, 46202
About this study
Official title: Protection of Renal Function After Liver Transplant Using Everolimus Monotherapy as the 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 have near normal kidney function prior to liver transplantation. Other investigators have already shown a benefit in terms of renal function with introduction of Everolimus with reduced-exposure tacrolimus at 1 month after liver transplantation, this benefit has been shown was maintained to 3 years in patients who continued Everolimus therapy with comparable efficacy and no late safety concerns. Investigators in this trial are proposing to advance this approach further by completely eliminating Tacrolimus from patients' immunosuppression protocol. The rationale for this approach is based on a unique induction immunosuppression protocol.
Read more
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. By completely eliminating Tacrolimus, investigators believe that there may be further benefit in terms of renal function. Additionally, Everolimus is known to induce tolerance in transplant recipients. Tolerant patients do not require immunosuppression to accept transplant organs.
The long-term efficacy and safety of Everolimus monotherapy as the maintenance immunosuppression in patients receiving rATG induction is unknown.
Primary Aim: Assess the effect of Everolimus monotherapy versus Tacrolimus monotherapy on long term renal function measured by Glomerular Filtration Rate (GFR).
Read the detailed description
Following enrollment, subjects will be randomized at one month post transplant to Tacrolimus (control) or to Everolimus (study) as 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 nasogastric (NG) x 1 dose 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:
Tacrolimus (FK / Prograf®) (titrated to a goal trough of 6 - 8 ng/mL).
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) + low dose Tacrolimus (target trough levels 3-5 ng/mL) (study arm). The control arm will be maintained on the Tacrolimus monotherapy (target trough levels 6-8 ng/mL).
At 3 months, patients in the study arm will be gradually weaned off of Tacrolimus over a period of one month to remain on Everolimus monotherapy (target trough levels 4-8 ng/mL). Patients in the control arm will remain on tacrolimus monotherapy (target trough levels 6-8 ng/mL).
Complete blood counts, liver function panels, and drug levels will be monitored as done 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, endoscopic retrograde cholangiopancreatography (ERCP), biopsy as needed by clinical situation as SOC.
For characterizing operational tolerance in these patients, investigators will use a 13#gene set to predict liver transplant tolerance has been identified and validated by others.
- 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
Tacrolimus (FK / Prograf) titrated to a goal trough of 6 - 8 ng/ml
EverolimusDrug
Also called Zortress
Everolimus monotherapy - target trough levels 4 - 8 ng/ml as maintenance immunosuppression
| Study group | Role | What they receive |
|---|---|---|
| Control Arm | Active comparator | Tacrolimus as maintenance immunosuppression Receives: Drug: Tacrolimus |
| Study Arm | Experimental | Everolimus monotherapy maintenance immunosuppression Receives: Drug: Everolimus |
What is being measured
The primary outcome is the main question the study is designed to answer.
Long-Term Renal Function With Tacrolimus Monotherapy
Glomerular Filtration Rate
Measured: 36 months post-transplant
Long-Term Renal Function With Everolimus Monotherapy
Glomerular Filtration Rate
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 posted21 Aug 2019
- Study start9 May 2019
- Primary completion2 Jul 2020
- Study completion2 Jul 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
- Masking
- None (open label)
- Enrolment
- 14 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
- NCT04063865
- Sponsor's protocol ID
- 1807401376
- Status last verified
- Apr 2023
- First submitted
- 19 Aug 2019
- Last updated
- 23 May 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- 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 23 May 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Protection of Renal Function After Liver Transplant Using Everolimus Monotherapy as the Immunosuppression Regimen
- ClinicalTrials.gov ID
- NCT04063865
- Acronym / sponsor ID
- 1807401376
- 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
- 14 participants (actual)
- Lead sponsor
- Indiana UniversityUniversity, hospital or other
- Study start
- 9 May 2019 (actual)
- Primary completion
- 2 Jul 2020 (actual)
- Study completion
- 2 Jul 2020 (actual)
- First posted
- 21 Aug 2019 (actual)
- Results
- Posted 23 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 have near normal kidney function prior to liver transplantation. Other investigators have already shown a benefit in terms of renal function with introduction of Everolimus with reduced-exposure tacrolimus at 1 month after liver transplantation, this benefit has been shown was maintained to 3 years in patients who continued Everolimus therapy with comparable efficacy and no late safety concerns. Investigators in this trial are proposing to advance this approach further by completely eliminating Tacrolimus from patients' immunosuppression protocol. The rationale for this approach is based on a unique induction immunosuppression protocol.
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. By completely eliminating Tacrolimus, investigators believe that there may be further benefit in terms of renal function. Additionally, Everolimus is known to induce tolerance in transplant recipients. Tolerant patients do not require immunosuppression to accept transplant organs.
The long-term efficacy and safety of Everolimus monotherapy as the maintenance immunosuppression in patients receiving rATG induction is unknown.
Primary Aim: Assess the effect of Everolimus monotherapy versus Tacrolimus monotherapy on long term renal function measured by Glomerular Filtration Rate (GFR).
Detailed description
Following enrollment, subjects will be randomized at one month post transplant to Tacrolimus (control) or to Everolimus (study) as 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 nasogastric (NG) x 1 dose 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:
Tacrolimus (FK / Prograf®) (titrated to a goal trough of 6 - 8 ng/mL).
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) + low dose Tacrolimus (target trough levels 3-5 ng/mL) (study arm). The control arm will be maintained on the Tacrolimus monotherapy (target trough levels 6-8 ng/mL).
At 3 months, patients in the study arm will be gradually weaned off of Tacrolimus over a period of one month to remain on Everolimus monotherapy (target trough levels 4-8 ng/mL). Patients in the control arm will remain on tacrolimus monotherapy (target trough levels 6-8 ng/mL).
Complete blood counts, liver function panels, and drug levels will be monitored as done 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, endoscopic retrograde cholangiopancreatography (ERCP), biopsy as needed by clinical situation as SOC.
For characterizing operational tolerance in these patients, investigators will use a 13#gene set to predict liver transplant tolerance has been identified and validated by others.
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
| Arm | Type | Receives |
|---|---|---|
| Control Arm | Active comparator | Drug: TacrolimusTacrolimus as maintenance immunosuppression |
| Study Arm | Experimental | Drug: EverolimusEverolimus monotherapy 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
- Normal baseline renal dysfunction (GFR > 60 mL/min)
- Rabbit anti-thymocyte globulin (rATG) induction (cumulative dose 1.5 - 5 mg/kg)
- Indication for transplant: ethanol, hepatitis C, or nonalcoholic steatohepatitis or any combination of these
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 months prior to transplantation
- Insurance company unwilling to pay for the cost of the everolimus or patient does not qualify for the Novartis Patient Assistance Program.
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: PrografTacrolimus (FK / Prograf) titrated to a goal trough of 6 - 8 ng/ml | Drug | Control Arm |
| EverolimusAlso: ZortressEverolimus monotherapy - target trough levels 4 - 8 ng/ml as maintenance immunosuppression | Drug | Study Arm |
Primary outcome
Long-Term Renal Function With Tacrolimus Monotherapy
Time frame: 36 months post-transplant
Glomerular Filtration Rate
Long-Term Renal Function With Everolimus Monotherapy
Time frame: 36 months post-transplant
Glomerular Filtration Rate
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 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 23 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 23 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?
Long-Term Renal Function With Tacrolimus Monotherapy (time frame: 36 months post-transplant). The study lists 2 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 23 May 2023.