Orthotopic Liver TransplantPhase 2NCT01998789
Everolimus Post Orthotopic Liver Transplant
A Phase 2 study testing Everolimus and Standard Tacrolimus in people with Orthotopic Liver Transplant, run by Tomoaki Kato at 1 site in United States.
Trial summary
The purpose of this study is to evaluate the efficacy of an everolimus conversion (EVR) protocol as compared to the standard tacrolimus (TAC) based protocol in liver transplant recipients, as determined by renal function, rejection rates, and progression to fibrosis (in HCV positive subjects). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Orthotopic Liver Transplant
- What is being tested?
- Everolimus and Standard Tacrolimus
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 50 participants
- Where
- 1 siteUnited States
- Study dates
- Oct 2013to Feb 2019
- Phase
- Phase 2
- Are there results?
- None posted in the registry
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
- Ability and willingness to provide informed consent and adhere to study regimen
- Recipients of primary liver transplant from deceased or living donor
- 18 years of age or greater
- Lab Model For End-Stage Liver Disease (MELD) score ≤ 30
- Abbreviated Modification of Diet in Renal Disease (MDRD) eGFR ≥ 30 mL/min/1.73
Who cannot join
- Recipient of multiple solid or organ transplant, or have previously received and organ transplant
- Women of child-bearing potential unless they are willing to participate in adequate contraception methods as outlined in the study.
- HIV infection (results obtained 6 months prior to screening is acceptable)
- Severe hypercholesterolemia (> 350 mg/dL) or hypertriglyceridemia (> 500 mg/dL) within 30 days prior to baseline.
- Thrombocytopenia (platelets < 50,000/mm3)
- Absolute neutrophil count of < 1000/mm3 or white blood cell count of < 2000/mm3
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- Subjects in a critical care unit requiring life support measures such as mechanical ventilation, dialysis, requirement of vasopressor agents
- Liver allograft is functioning at an unacceptable level as defined by the Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Total Bilirubin levels > 3 times upper limit of normal (ULN) and Alkaline Phosphatase (AlkP) and Gamma-glutamyltransferase (GGT) levels > 5 times ULN
- Diagnosis of autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis
- Hepatocellular carcinoma with evidence of macrovascular invasion on explanted liver or evidence of extrahepatic spread
- Inability to take medications by mouth
- Renal insufficiency, as defined by abbreviated MDRD eGFR < 30 mL/min/1.73m2, or requirement of dialysis, that does not recover prior to baseline
- Episode of acute rejection requiring antibody therapy or more than one steroid treated episode of acute rejection
- Subjects with a confirmed spot urine protein/creatinine ratio that indicates ≥1g/24h of proteinuria.
- Subtherapeutic trough levels of tacrolimus during the week prior to baseline (subject must have at least one tacrolimus level ≥ 8 ng/mL)
- The presence of thrombosis via Doppler ultrasound of the major hepatic arteries, major hepatic veins, portal vein and inferior vena cava.
- Presence of clinically significant wound
Trial locations and contacts
1 site in 1 country.
Theresa Lukose, PharmD contact
United States1 site, 1 recruiting
- Recruiting
Columbia University Medical Center-NYPH
New York, New York, 10032
Tomoaki Kato, M.D, tk2388@columbia.edu
Theresa Lukose, PharmD, tt2103@columbia.edu
About this study
Official title: A Single Center, Open-label, Randomized, Controlled Pilot Trial to Evaluate the Efficacy and Safety of Everolimus Conversion Versus Standard Immunosuppression in Liver Transplant Recipients
The purpose of this study is to evaluate the efficacy of an everolimus conversion (EVR) protocol as compared to the standard tacrolimus (TAC) based protocol in liver transplant recipients, as determined by renal function, rejection rates, and progression to fibrosis (in HCV positive subjects). Additionally, safety profile and tolerability of these regimens will be assessed.
Read the detailed description
The mainstay of maintenance immunosuppression post-transplantation includes a calcineurin inhibitor, either cyclosporine or tacrolimus. The introduction of calcineurin inhibitors led to a significant improvement in graft and patient outcomes post solid organ transplantation. However, one of the severe limitations of this class of drugs, is its associated nephrotoxicity. Data from the Scientific Registry of Transplant Recipients reveal that the incidence of stage 4 chronic kidney disease or stage 5 Chronic Kidney Disease (CKD) after Orthotopic Liver Transplantation (OLT) at 1, 3, and 5 years is 8%, 14%, and 18%, respectively, increasing to approximately 25% by 10 years after transplantation.Furthermore, renal dysfunction is associated with a four-fold increase in patient mortality post solid organ transplantation.
Several calcineurin inhibitor sparing and minimizing regimens have been studied. Most recently, in the phase III, randomized study in de novo liver transplant recipients,demonstrated significantly improved renal function in the tacrolimus minimization arm (everolimus plus tacrolimus one year post transplant.In fact superior renal function was achieved with the tacrolimus minimization arm one month after randomization and was maintained to Month 12. With this pilot study, we aim to compare the efficacy of the standard immunosupression post liver transplant with Tacrolimus and Mycophenolic acid (Myfortic)with calcineurin sparing regimen using the combination of everolimus and enteric coated mycophenolic acid, as determined by the estimated Glomerular filtration rate (GFR) at one year post transplant, with acceptable rates of biopsy proven rejection.
- Conditions
- Orthotopic Liver Transplant
- Being tested
- Everolimus, Standard Tacrolimus
- Keywords
- Liver Transplantation, Everolimus, Immunosuppression
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EverolimusDrug
Also called Zortress
Everolimus will be initiated within 24 hours of baseline at a dose of 1 mg po BID (2 mg/day).
Standard TacrolimusDrug
Also called Prograf
Subjects will be maintained on standard maintenance immunosuppression per local protocol, consisting of a tacrolimus plus enteric coated mycophenolic acid. Oral corticosteroids may not be eliminated sooner than 180 days post transplantation.
Tacrolimus doses will be adjusted based on local lab results of tacrolimus trough levels.
| Study group | Role | What they receive |
|---|---|---|
| Everolimus Conversion Arm | Experimental | Everolimus will be initiated within 24 hours of baseline at a dose of 1 mg po BID (2 mg/day). Therapeutic Drug Monitoring will be performed throughout the study. Tacrolimus should be eliminated when the everolimus target range has been reached. Complete tacrolimus elimination will not occur earlier than 90 days post transplant and no later than 120 days post transplant. Enteric coated mycopenolic acid will be maintained for the duration of the study. Oral corticosteroids may not be eliminated sooner than 180 days post transplantation.
Everolimus doses will be adjusted based on local lab results of everolimus trough levels. Receives: Drug: Everolimus |
| Standard Tacrolimus Immunosuppresion Arm | Active comparator | Subjects will be maintained on standard maintenance immunosuppression per local protocol, consisting of a tacrolimus plus enteric coated mycophenolic acid. Oral corticosteroids may not be eliminated sooner than 180 days post transplantation.
Tacrolimus doses will be adjusted based on local lab results of tacrolimus trough levels. Receives: Drug: Standard Tacrolimus |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in estimated Glomerular Filtration Rate (eGFR)
Comparison of change in Renal function, as measured by eGFR from baseline to 12 months post liver transplantation, in subjects maintained on an everolimus conversion regimen versus those maintained on a standard tacrolimus based regimen.
Measured: Baseline and 12 months post transplant
Secondary outcomes (4)
Change in estimated Glomerular Filtration Rate (eGFR)
- Comparison of renal function, as measured eGFR from baseline to 24 months post liver transplantation, in subjects maintained on an everolimus conversion regimen versus those maintained on a standard tacrolimus based regimen.
- To compare the incidence of renal insufficiency, defined as GFR<30 or need for dialysis at 12 months and 24 months post liver transplantation, in subjects maintained on an everolimus conversion regimen versus those maintained on a standard tacrolimus based regimen.
Measured: Baseline and 24 months post liver transplantation
Proportion of HCV patients who develop stage 2 of 4 or greater fibrosis, liver failure, or fibrosing cholestatic hepatitis (FCH) at month 12 and 24
To determine whether everolimus conversion post liver transplantation reduces progression of fibrosis at 12 and 24 months post transplant as compared to standard tacrolimus based immunosuppression in liver transplant recipients with Hepatitis C as measured by:
Proportion of patients who develop stage 2 of 4 or greater fibrosis, liver failure, or fibrosing cholestatic hepatitis (FCH) at month 12 and 24
Measured: Up to 24 months post liver transplantation
Composite Efficacy Failure Rate
To compare the composite efficacy failure rates of treated biopsy proven acute rejection, graft loss, death, or loss to follow up with Everolimus conversion arm to standard immunosuppression with Tacrolimus based arm at 12 and 24 months after liver transplant.
To compare each component of the composite efficacy failure rates between Everolimus conversion and standard Tacrolimus arm.
To compare the composite graft failure or death or loss of follow up between the two arms.
To Evaluate acute rejection by incidence, time to interval and severity.
Measured: Up to 24 months
Incidence of Hepatocellular Carcinoma (HCC) Recurrence
In subjects with Hepatocellular carcinoma (HCC), to compare the incidence of HCC recurrence at 12 months post transplantation between the Everolimus conversion arm and the standard tacrolimus based arm, as evaluated by radiological studies, biopsy findings, and/or AFP levels.
Measured: Up to 12 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 posted2 Dec 2013 (estimated)
- Study startOct 2013
- Primary completionJun 2018 (estimated)
- Study completionFeb 2019 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Orthotopic Liver TransplantStudies of the same condition, open and under way.
- 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
- 50 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Tomoaki Kato
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Tomoaki Kato, Columbia University
- Investigators
- Tomoaki Kato, MD, Principal investigator, Columbia University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01998789
- Sponsor's protocol ID
- AAAL1602
- Status last verified
- Aug 2017
- First submitted
- 25 Nov 2013
- Last updated
- 10 Aug 2017
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 10 Aug 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Single Center, Open-label, Randomized, Controlled Pilot Trial to Evaluate the Efficacy and Safety of Everolimus Conversion Versus Standard Immunosuppression in Liver Transplant Recipients
- ClinicalTrials.gov ID
- NCT01998789
- Acronym / sponsor ID
- AAAL1602
- Conditions
- Orthotopic Liver Transplant
- Keywords
- Liver Transplantation, Everolimus, Immunosuppression
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 50 participants (estimated)
- Lead sponsor
- Tomoaki KatoUniversity, hospital or other
- Study start
- Oct 2013
- Primary completion
- Jun 2018 (estimated)
- Study completion
- Feb 2019 (estimated)
- First posted
- 2 Dec 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to evaluate the efficacy of an everolimus conversion (EVR) protocol as compared to the standard tacrolimus (TAC) based protocol in liver transplant recipients, as determined by renal function, rejection rates, and progression to fibrosis (in HCV positive subjects). Additionally, safety profile and tolerability of these regimens will be assessed.
Detailed description
The mainstay of maintenance immunosuppression post-transplantation includes a calcineurin inhibitor, either cyclosporine or tacrolimus. The introduction of calcineurin inhibitors led to a significant improvement in graft and patient outcomes post solid organ transplantation. However, one of the severe limitations of this class of drugs, is its associated nephrotoxicity. Data from the Scientific Registry of Transplant Recipients reveal that the incidence of stage 4 chronic kidney disease or stage 5 Chronic Kidney Disease (CKD) after Orthotopic Liver Transplantation (OLT) at 1, 3, and 5 years is 8%, 14%, and 18%, respectively, increasing to approximately 25% by 10 years after transplantation.Furthermore, renal dysfunction is associated with a four-fold increase in patient mortality post solid organ transplantation.
Several calcineurin inhibitor sparing and minimizing regimens have been studied. Most recently, in the phase III, randomized study in de novo liver transplant recipients,demonstrated significantly improved renal function in the tacrolimus minimization arm (everolimus plus tacrolimus one year post transplant.In fact superior renal function was achieved with the tacrolimus minimization arm one month after randomization and was maintained to Month 12. With this pilot study, we aim to compare the efficacy of the standard immunosupression post liver transplant with Tacrolimus and Mycophenolic acid (Myfortic)with calcineurin sparing regimen using the combination of everolimus and enteric coated mycophenolic acid, as determined by the estimated Glomerular filtration rate (GFR) at one year post transplant, with acceptable rates of biopsy proven rejection.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Everolimus Conversion Arm | Experimental | Drug: EverolimusEverolimus will be initiated within 24 hours of baseline at a dose of 1 mg po BID (2 mg/day). Therapeutic Drug Monitoring will be performed throughout the study. Tacrolimus should be eliminated when the everolimus target range has been reached. Complete tacrolimus elimination will not occur earlier than 90 days post transplant and no later than 120 days post transplant. Enteric coated mycopenolic acid will be maintained for the duration of the study. Oral corticosteroids may not be eliminated sooner than 180 days post transplantation. Everolimus doses will be adjusted based on local lab results of everolimus trough levels. |
| Standard Tacrolimus Immunosuppresion Arm | Active comparator | Drug: Standard TacrolimusSubjects will be maintained on standard maintenance immunosuppression per local protocol, consisting of a tacrolimus plus enteric coated mycophenolic acid. Oral corticosteroids may not be eliminated sooner than 180 days post transplantation. Tacrolimus doses will be adjusted based on local lab results of tacrolimus trough levels. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Ability and willingness to provide informed consent and adhere to study regimen
- Recipients of primary liver transplant from deceased or living donor
- 18 years of age or greater
- Lab Model For End-Stage Liver Disease (MELD) score ≤ 30
- Abbreviated Modification of Diet in Renal Disease (MDRD) eGFR ≥ 30 mL/min/1.73
Key exclusion criteria (17 listed)
- Recipient of multiple solid or organ transplant, or have previously received and organ transplant
- Women of child-bearing potential unless they are willing to participate in adequate contraception methods as outlined in the study.
- HIV infection (results obtained 6 months prior to screening is acceptable)
- Severe hypercholesterolemia (> 350 mg/dL) or hypertriglyceridemia (> 500 mg/dL) within 30 days prior to baseline.
- Thrombocytopenia (platelets < 50,000/mm3)
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 |
|---|---|---|
| EverolimusAlso: ZortressEverolimus will be initiated within 24 hours of baseline at a dose of 1 mg po BID (2 mg/day). | Drug | Everolimus Conversion Arm |
| Standard TacrolimusAlso: PrografSubjects will be maintained on standard maintenance immunosuppression per local protocol, consisting of a tacrolimus plus enteric coated mycophenolic acid. Oral corticosteroids may not be eliminated sooner than 180 days post transplantation. Tacrolimus doses will be adjusted based on local lab results of tacrolimus trough levels. | Drug | Standard Tacrolimus Immunosuppresion Arm |
Primary outcome
Change in estimated Glomerular Filtration Rate (eGFR)
Time frame: Baseline and 12 months post transplant
Comparison of change in Renal function, as measured by eGFR from baseline to 12 months post liver transplantation, in subjects maintained on an everolimus conversion regimen versus those maintained on a standard tacrolimus based regimen.
4 secondary outcomes
Change in estimated Glomerular Filtration Rate (eGFR)
Time frame: Baseline and 24 months post liver transplantation
Proportion of HCV patients who develop stage 2 of 4 or greater fibrosis, liver failure, or fibrosing cholestatic hepatitis (FCH) at month 12 and 24
Time frame: Up to 24 months post liver transplantation
Composite Efficacy Failure Rate
Time frame: Up to 24 months
Incidence of Hepatocellular Carcinoma (HCC) Recurrence
Time frame: Up to 12 months post transplant
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Aug 2017.
- Individual participant dataSharing planned: Undecided
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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.
Theresa Lukose, PharmD contact
Tomoaki Kato, MD principal investigator
Columbia University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Everolimus and Standard Tacrolimus in people with Orthotopic Liver Transplant, run by Tomoaki Kato 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 5 inclusion and 17 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: status not confirmed, as of the sponsor's last update on 10 Aug 2017. 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 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?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Theresa Lukose, PharmD (tt2103@columbia.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in estimated Glomerular Filtration Rate (eGFR) (time frame: Baseline and 12 months post transplant). 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 10 Aug 2017.