A Study in Adults on Pre LT Dialysis With Basiliximab, Delayed Tacrolimus (TAC), Mycophenolate (MMF), Steroids (Grp 1) vs. Basiliximab, Delayed TAC, MMF, Steroids, With Everolimus 30d Post LT(Grp 2), vs. TAC, MMF, Steroids (Grp 3).
Phase: PHASE4
Conditions: Asses Immunosuppression Modulation on Renal Recovery Post LT
Sponsor: Fady M Kaldas, M.D., F.A.C.S.

Official Title: 
A Study in Adults on Pre-LT Dialysis With Basiliximab, Delayed Tacrolimus (TAC), 
Mycophenolate (MMF), and Steroids (Group 1) vs. Basiliximab, Delayed TAC, MMF, Steroids, 
With Everolimus 30 Days Post-LT (Group 2) vs. TAC, MMF, and Steroids (Group 3) 
NCT Number: 
NCT04104438 
Document Date: 
November 7, 2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Study Synopsis 
 
TITLE 
An single center, open label, randomized, prospective, phase 4 study of induction and 
maintenance immunosuppression in adult subjects age >18 years undergoing orthotopic 
liver transplantation (OLT) with basiliximab, delayed dose tacrolimus plus mycophenolate 
mofetil and standard of care (SOC) corticosteroids (Group 1) versus basiliximab, delayed 
dose tacrolimus plus mycophenolate mofetil, SOC corticosteroids, with addition of 
delayed maintenance everolimus at one month post OLT with subsequent mycophenolate 
mofetil minimization (Group 2) versus standard dose tacrolimus plus mycophenolate 
mofetil plus SOC corticosteroids (Group 3; control) with a high risk of developing renal 
dysfunction following OLT or with concomitant renal dysfunction prior to OLT.  
 
OBJECTIVES 
To assess the efficacy and safety of basiliximab, delayed dose tacrolimus plus 
mycophenolate mofetil, and SOC corticosteroids versus basiliximab, delayed dose 
tacrolimus plus mycophenolate mofetil, and SOC corticosteroids and addition of delayed 
everolimus/mycophenolate minimization at one month post OLT compared to standard 
triple immunosuppression (tacrolimus, mycophenolate mofetil and corticosteroids) for 
prevention of acute organ rejection in liver transplant recipients with a high risk of 
developing renal dysfunction following OLT or with concomitant renal dysfunction prior to 
OLT.   
 
STUDY DESIGN: single center, randomized, prospective, pilot 
 
DRUG THERAPY  
Group 1 
Basiliximab  
o Dose #1: 20mg IV within 2 hours of transplant  
o Dose #2: 20mg IV Post-operative day #4 
 
Tacrolimus (with basiliximab induction) 

o Beginning day #5 post-transplant or when SCr < 1.8 mg/dl (subjects off 
dialysis) to six months: 0.03-0.1mg/kg q12h PO to maintain whole blood 
trough concentration of 4-6ng/mL 
 
Mycophenolate mofetil 
o 500 mg po bid 
 
Corticosteroids (SOC):  Per UCLA protocol 
Post-operative taper: 
o Post-op day 1- 
methylprednisolone 50mg IVP Q6H 
o Post-op day 2- 
methylprednisolone 40mg IVP Q6H 
o Post-op day 3- 
methylprednisolone 30mg IVP Q6H 
o Post-op day 4- 
methylprednisolone 20mg IVP Q6H 
o Post-op day 5- 
methylprednisolone 20mg IVP Q12H 
o Post-op day 6- 
methylprednisolone 10mg IVP Q12H  
until taking PO, then change to: prednisone 20mg PO QAM 
 
Group 2 
Basiliximab  
o Dose #1: 20mg IV within 2 hours of transplant  
o Dose #2: 20mg IV Post-operative day #4 
 
Tacrolimus (with basiliximab induction) 
o Beginning day #5 post-transplant or when SCr < 1.8 mg/dl (subjects off 
dialysis) to POD 30: 0.03-0.1mg/kg q12h PO to maintain whole blood trough 
concentration of 4-6ng/mL 
o POD 31; reduce to tacrolimus to 2-5ng/mL in presence of everolimus levels 
3-8 ng/mL 
 
Mycophenolate mofetil 
o 500 mg po bid up to POD 30:  reduce mycophenolate mofetil following 
achievement of steady state everolimus (POD 35) as clinically indicated 
 
Corticosteroids (SOC):  Per UCLA protocol 
Post-operative taper: 

o Post-op day 1- 
methylprednisolone 50mg IVP Q6H 
o Post-op day 2- 
methylprednisolone 40mg IVP Q6H 
o Post-op day 3- 
methylprednisolone 30mg IVP Q6H 
o Post-op day 4- 
methylprednisolone 20mg IVP Q6H 
o Post-op day 5- 
methylprednisolone 20mg IVP Q12H 
o Post-op day 6- 
methylprednisolone 10mg IVP Q12H  
until taking PO, then change to: prednisone 20mg PO QAM 
 
Everolimus (delayed) 
o Add by POD 30: 1 mg po bid and adjusted to maintain whole blood trough 
concentrations of 3-8 ng/ml. 
 
Group 3 (control): 
Tacrolimus (without basiliximab induction) 
o Beginning day #1 post-transplant to six months: 0.03-0.1mg/kg q12h po to 
maintain whole blood trough concentration of 5-12ng/mL 
o Six months to one year: maintain whole blood trough concentration of 5-
10ng/mL 
 
Mycophenolate mofetil 
o 500 mg po bid 
 
 
Corticosteroids (SOC):  Per UCLA protocol 
Post-operative taper: 
o Post-op day 1- 
methylprednisolone 50mg IVP Q6H 
o Post-op day 2- 
methylprednisolone 40mg IVP Q6H 
o Post-op day 3- 
methylprednisolone 30mg IVP Q6H 
o Post-op day 4- 
methylprednisolone 20mg IVP Q6H 
o Post-op day 5- 
methylprednisolone 20mg IVP Q12H 
o Post-op day 6- 
methylprednisolone 10mg IVP Q12H  
until taking PO, then change to:  prednisone 20mg PO QAM 
 
PATIENT POPULATION 

In a 2:2:1 fashion, 90 subjects (group 1: n=36; group 2:  n=36; group 3: n=18) will be 
randomized at UCLA Medical Center.  Each subject will be followed for 6 months post-
transplant. 
 
PRIMARY ENDPOINTS 
• Assessment of the nephroprotective effects of everolimus in combination with 
simulect, or simulect alone following OLT at months 2, 3, 4, 5 and 6.  
 
SECONDARY ENDPOINTS 
• Mean serum creatinine, eGFR (MDRD) at weeks 1, 2, 4, 8, 12, 16, 20 and 24  
• 1, 3 month and 6 month cumulative incidence of acute allograft rejection 
episodes, steroid resistant rejection episodes, dialysis requirements 
• Incidence of death and/or graft failure at 6 months  
• Tolerability and side effect profile of the combination drug therapies 
• Incidence of infectious complications 
• Time to first episode of acute rejection 
• Refractory rejection episodes (requiring immunosuppression beyond T cell 
depletion) 
• Rejection episodes per subjects 
• Number of subjects requiring full-dose calcineurin inhibitor rescue therapy 
• Monitor CD25 cell count for 3 months 
• Economic analysis to determine cost-effectiveness of induction therapy with IL-
2 monoclonal antibody 
• Economic analysis to determine cost-effectiveness of delayed therapy with 
mTOR 
 
A three arm, single center, randomized, prospective, pilot trial of induction and 
maintenance immunosuppression with basiliximab, delayed dose tacrolimus plus 
mycophenolate mofetil, and SOC corticosteroids versus immunosuppression with 
basiliximab, delayed dose tacrolimus plus mycophenolate mofetil, and SOC 
corticosteroids with delayed addition of everolimus and mycophenolate 
minimization versus standard dose tacrolimus and mycophenolate mofetil plus 
corticosteroids in patients undergoing orthotopic liver transplantation (OLT) with 
concomitant renal dysfunction 
 
Introduction (Background and Rationale) 

Renal disease is commonly found in patients undergoing liver transplant evaluation.  In 
the terminal stages of liver disease, approximately 75% of patients develop oligoanuric 
renal failure. [1] One study of 102 liver allograft recipients revealed 25% experienced renal 
impairment before transplantation and 67% after transplantation.[2] This study also 
showed that pre-transplantation renal dysfunction was an independent predictor of 
postoperative mortality. Numerous factors may affect renal function in the end-stage liver 
disease patient. Some include hepatorenal syndrome, the complexity of the operation for 
liver transplantation, and the potential for postoperative graft dysfunction.  [3,4] 
Furthermore, the incidence of short term renal dysfunction can be linked to the pre-
transplant model for end stage liver disease (MELD) score.  Specifically, elevations in pre-
transplant serum creatinine which is one of three factors used to calculate the MELD 
score for organ allocation are associated with reduction in renal function and are a 
negative predictive factor for patients with cirrhosis (and after OLT). [4]   
 
Despite extensive knowledge of post operative renal dysfunction in liver transplant 
recipients, chronic renal failure following liver transplantation remains one of the most 
challenging complications with chronic renal failure occurring in up to 18-20% of OLT 
recipients after five years [5,6].  The etiology of altered renal function following OLT is 
complex, but one of the most important risk factors is the nephrotoxic effects of the 
therapeutic agents required to guard against rejection, namely long term calcineurin 
inhibitor usage.  [1,7] Tacrolimus (TAC) and cyclosporin (CYA), are known as the 
calcineurin inhibitors (CNIs).  These immunosuppressive drugs are routinely used to help 
prevent rejection following solid organ transplantation. Along with other advances, these 
agents have helped most liver transplant centers achieve one year survival rates higher 
than 85% because of better clinical management.[8]  Nephrotoxicity is the most notable 
adverse effect associated with CNI therapy.  CNIs can cause long-term structural and 
functional changes to the kidney, contributing to the long term problems seen in transplant 
patients. [9-11] Histologically, striped tubulointerstitial fibrosis, tubular atrophy, and 
afferent arteriolopathy are noted. [9,12-14]  CNIs have been reported to elucidate 
transient reductions in renal plasma flow and glomerular filtration rate that results from 
acute, reversible renal hypoperfusion with the greatest change in GFR in the first 3-6 
months.  [15] This continual renal hypoperfusion might explain the structural changes and 
long term functional deterioration of the pre-glomerular, afferent arterioles and be a critical 
indicator of future problems. 
 
Therefore, OLT recipients with pre-existing renal impairment or high (renal driven) MELD 
scores could benefit from alternative immunosuppressive strategies in the immediate and 
long term post-transplant settings.  Immunosuppressive regimens that are calcineurin 

sparing, calcineurin free or regimens that add novel agents such as mTOR inhibitors (e.g. 
everolimus) at specific times following transplant in order to reduce CNI exposure or 
withdraw them entirely have been suggested and studied on a limited basis. [16-20] 
 
Recently at our center, we completed a pilot trial in 60 adult OLT recipients in which we 
compared our standard triple immunosuppressive therapy with TAC plus myfortic and a 
standard of care corticosteroid taper to induction therapy with basiliximab with delayed 
use of tacrolimus therapy (until post-operative day 7), combined with myfortic and a rapid 
corticosteroid taper.  The delay in tacrolimus therapy in the basiliximab induction group 
resulted in a mild improvement in renal function by three months following transplant while 
maintaining adequate immunosuppression to prevent acute rejection.  This study was 
limited in the number of subjects enrolled and suffered from an inability to further reduce 
CNI exposure and perhaps enhance renal recovery or improvement following OLT.  Thus 
additional CNI sparing agents could benefit these recipient with respect to enhancing 
renal function over time. 
 
Everolimus is an mTOR inhibitor that is a structural derivative of sirolimus, with a distinct 
pharmacokinetic profile (shorter half-life and twice a day dosing).  Clinical experience 
showed that a pharmacokinetic interaction of tacrolimus on everolimus may be less than 
with cyclosporine or even absent, and that the combination of everolimus and tacrolimus 
was safe and well tolerated with no new safety risks identified. [21, 22]  
It has been approved for use in liver transplant recipients in combination with 
corticosteroids and reduced dose tacrolimus.  Approval was based on a large study 
(n=719) in which delayed everolimus (introduced POD 30) with reduced dose tacrolimus 
(39% reduction of tacrolimus) showed comparable efficacy (incidence of biopsy proven 
acute  rejection, graft loss or death) and had superior renal function as early as 1 month 
compared to standard dose tacrolimus.  [23]  Additionally, several small or retrospective 
studies have reported the use of everolimus in OLT recipients in combination with CNI 
reduction or as a CNI withdrawal strategy. [24-26]   
 
Similar to the CNIs, everolimus administration includes trough level therapeutic drug 
monitoring (TDM). This practice has evolved largely due to the relatively narrow 
therapeutic window for immunosuppression, the considerable inter- and intraindividual 
pharmacokinetic variability, as well as the high incidence of drug-drug interactions 
resulting from hepatic metabolism via cytochrome P450 isoenzyme 3A4 (CYP3A4).  
Results in adults using therapeutic drug level monitoring of everolimus target an 
everolimus C-0h blood trough level of 3-8 ng/mL.   [27, 28] 

 
Previously, the risk of hepatic artery thrombosis (HAT), leading to an increased rate of 
patient death within the first 30 days post-transplantation, was identified as a concern 
after liver transplantation using sirolimus. [29] However, recent results suggest that 
sirolimus used at low doses or early after the immediate peri-operative period was not 
associated with HAT. [30] HAT has neither been associated with the use of everolimus. 
[31] However, the Phase III trial conducted in de novo adult whole liver transplantation 
implemented delayed everolimus administration (POD 30 ± 5 days) to limit the risk of drug 
induced HAT.  
 
Therefore, based on the available data and experience in OLT recipients and building on 
our previous UCLA pilot trial design and experience, the potential benefit from the 
introduction of delayed everolimus and improved renal function related to reduction of 
calcineurin inhibitors (CNI) over time and enhanced safety profile warrants additional 
investigation. 
 
Thus, we propose a randomized, prospective investigator initiated study that will compare 
basiliximab induction, delayed TAC exposure plus MMF and a SOC corticosteroid taper 
(group 1; n=36), compared to basiliximab induction, delayed TAC exposure plus MMF 
and a SOC corticosteroid taper with a delayed everolimus facilitated CNI reduction at 
POD 30 and mycophenolate minimization to further enhance renal function (group 2; 
n=36) versus control (standard dose TAC plus MMF and standard of care corticosteroid 
taper; group 3; n=18).  
 
Clearly, the primary objective assesses rate and severity of rejection, allograft loss and 
death as well as post-operative renal function (measured as estimated GFR).   The 
proposed study will also evaluate the mTOR class effects (e.g., dyslipidemia, impaired 
wound healing and proteinuria) and in addition, it will monitor closely the potential safety 
effects of chronic mTOR inhibitor therapy upon infectious complications such as CMV, 
and HBV and HCV. 
 
Purpose 
Primary Objectives 
• To evaluate the evolution of renal function assessed by dialysis independence and 
time to independence from dialysis. 

 
Secondary Objectives  
 
• 
Glomerular Filtration Rate (eGFR); Cockcroft and Gault (MDRD) 
• 
To determine the incidence of confirmed acute rejection episodes in patients undergoing 
orthotopic liver transplant at 1, 3 and 6 months post-transplant 
• 
To determine the tolerability and adverse event profile of basiliximab, delayed dose 
tacrolimus, mycophenolate mofetil, SOC corticosteroids and Everolimus during the first 
six months post-transplant  
• 
To determine the incidence of infectious complications during the first six months post-
transplant 
• 
To determine the time to the first episode of acute rejection  
• 
To determine the severity of each acute rejection episode 
• 
To determine the incidence of death and/or graft failure within the first six months post-
transplant 
• 
To determine the number of patients requiring full dose CNI rescue therapy 
• 
To determine the mean serum creatinine concentration and eGFR:  Cockcroft and 
Gault (MDRD) at weeks 1, 2, 4, 8, 12, 16, 20 and 24 post OLT 
• 
To monitor CD25 cell count for the first 3 months post-transplant 
• Economic analysis to determine cost-effectiveness of induction therapy with IL-2 
monoclonal antibody 
• Economic analysis to determine cost-effectiveness of delayed therapy with 
everolimus 
 
 
Efficacy objectives at 1, 2, 3, and 5 months after start of everolimus 
 
 
To assess: 
- 
Rate of composite efficacy failure of treated biopsy proven acute rejection 
(tBPAR), graft loss (GL) or death (D). 
- 
Time to event and severity of tBPAR. 
- 
Incidence and severity of all acute rejection. 
To evaluate: 
- 
Renal function over time assessed by mean change in eGFR by the Cockcroft 
and Gault (MDRD) from the start of everolimus. 
- 
Urinary protein/creatinine ratio at various time points 
- 
Incidence of and time to renal replacement therapy. 
 

Safety objectives 
To evaluate: 
- 
All AE/SAEs with emphasis on viral infections and reactivation (CMV, EBV, HIV, 
Hepatitis B and Hepatitis C), hematological and metabolic laboratory 
parameters, gastrointestinal side effects and malignancies. 
- 
Incidence of treatment-related side effects including incidence of new onset 
diabetes mellitus (NODM), serum/blood lipid panel, neurotoxicity and 
hypertension. 
- 
Incidence and reason (e.g. AE) for premature discontinuation of study 
medication, and premature withdrawal from the study. 
- 
Incidence and reason (e.g. AE) for dose interruption and dose adjustment of 
study medication. 
 
Rationale of dose/regimen, duration of treatment 
The immunosuppressant drugs, basiliximab, tacrolimus, mycophenolate mofetil, 
corticosteroids (methylprednisolone/prednisone), and everolimus are marketed drugs 
and their dosage and administration will be based on label recommendations and clinical 
standards of care  
 
Study Population 
The study population will consist of adult (age >18 years) male and female primary liver 
transplant recipients.  All patients will have received a liver allograft from a deceased 
donor.  
 
It is anticipated our center will need to screen approximately 140 male and female adult 
liver transplant recipients. Of these 140 liver allograft recipients, it is expected a minimum 
of 90 will fulfill the inclusion and none of the exclusion criteria at baseline and will be able 
to be randomized in a 2:2:1 manner to receive one of the three proposed 
immunosuppressive regimens.    
 
Inclusion Criteria at Baseline 
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 
1. A signed informed consent prior to patient participation in the study and before 
any assessment is performed. 
2. Patients who are able to take oral medication at 1 month post transplant 

3.  18 years old 
4. Undergoing first OLT 
5. Dialysis for 45 days or less at time of transplant 
6. Able and willing to conform to requirements of the study 
7. Able and willing to provide informed consent or have legally authorized representative 
who is able and willing to provide informed consent  
 
Exclusion Criteria 
1. < 18 years old 
2. Autoimmune liver disease, Primary Sclerosing Cholangitis, Primary Biliary 
Cirrhosis 
3. Dialysis greater than 45 days 
4. Receiving ATG, IVIG therapy, or sirolimus/everolimus around time of transplant 
or sirolimus/everolimus after transplant 
5. Unable to take oral medications at 1 month post transplant 
6. Participating in another clinical research study involving the evaluation of 
another investigational drug or device 
7. Documented allergy to basiliximab, TAC, MMF or any macrolide antibiotic. 
8. Presence of thrombosis of any major hepatic arteries 
9. Complex/high risk arterial reconstruction at any time (graft vessel patency by 
Doppler ultrasound confirmed and documented). 
10. Patients who are recipients of multiple solid organ transplants, (e.g., 
multivisceral or combined liver-kidney transplants), or have previously received 
an organ or tissue transplanted, or who received an ABO incompatible 
transplant. 
11. Patients who have severe hypercholesterolemia (>215 mg/dL; >5.5 mmol/L) or 
hypertriglyceridemia (>265 mg/dL; >3.0 mmol/L) at Baseline. 
12. Patients who have severe thrombocytopenia or neutropenia (platelet count >20 
and MLCs>1000)  
13. Patients who have any surgical or medical condition, which in the opinion of the 
investigator, might significantly alter the absorption, distribution, metabolism 
and excretion of study drugs 
14. Patients with a known hypersensitivity to the drugs used on study or their class, 
or to any of the excipients. 
15. Patients with clinically significant systemic infection 
16. Pregnant or nursing (lactating) female patients, where pregnancy is defined as 
the state of a female after conception and until the termination of gestation, 
confirmed by a positive βHCG laboratory test (>9 mIU/mL) at Baseline. 
 
Investigational Treatment 
Introduction and maintenance of everolimus 

Everolimus will be introduced at the earliest 1 month after liver transplantation for all 
patients to minimize the potential risks of wound healing and vascular complications of 
the graft. At the start of the treatment period (Day 1), patients will receive the first dose of 
everolimus (1 mg twice daily in 12 hr intervals) 
 
By Day 4, the everolimus dose will be adjusted to achieve targeted C-0h blood trough 
level between 3-8 ng/mL. All patients will continue to receive everolimus with CNI reduced 
dose for 6 months. Mycophenolate will be minimized as clinically indicated in subjects 
(group 2) receiving everolimus and tacrolimus.  
 
The dose of everolimus must be taken twice-daily, 12 hours apart, in the morning and 
evening dose AFTER tacrolimus administration (everolimus or tacrolimus dose 
administrations should not be more than 10 minutes apart). The morning or evening 
everolimus dose should be taken consistently either with or without food as the patient 
prefers. To prevent alteration of study drug absorption, grapefruit or grapefruit juice are 
not allowed throughout the study. 
 
Permitted dose adjustments and interruptions of study treatment 
For patients who are unable to tolerate the protocol-specified dosing scheme, dose 
adjustments and interruptions are permitted to allow the patient to continue on study drug. 
In general, in a first attempt to treat patients who have difficulties to tolerate their 
immunosuppressive regimen, symptomatic treatment should be considered. The 
following guidelines should be followed. 
 
Everolimus 
 
The recommended route of administration for everolimus is orally, therefore patients who 
are unable to take oral medications by 1 month post transplant will be excluded from the 
study. 
 
For patients for patients who are unable to tolerate the protocol-specified dosing scheme 
due to a decrease in the platelet count, a decrease in hemoglobin level, a decrease in 
white blood count, an increase in cholesterol level, an increase in triglyceride level, or 

other adverse events, dose adjustments are permitted in order to keep the patient on the 
study drug.  
 
The everolimus dose should be decreased by at least one third of the total daily dose of 
the study if a dose reduction is necessary. The everolimus C-0h blood trough level should 
still be kept ≥3 ng/mL.  Everolimus should be discontinued if a C-0h blood trough level ≥3 
ng/mL cannot be maintained due to toxicity or intolerable side-effects. The total daily dose 
should be adjusted by increasing or decreasing the dose depending on the C-0h blood 
trough level. If the C-0h blood trough level is <3 ng/mL, everolimus will be increased by 
doubling the dose and if the C-0h blood trough level is >8 ng/mL, the everolimus dose will 
be decreased by at least by 25 % of the daily dose. Interruption of study drug and/or 
temporarily everolimus C-0h blood trough level <3 ng/mL are up to the discretion of the 
investigator and the investigator has to assure for adequate immunosuppression, i.e. by 
compensating interruption and/or temporarily everolimus C-0h blood trough level <3 
ng/mL by the temporary introduction of a higher exposure of tacrolimus. 
 
Tacrolimus 
Tacrolimus will be administered either orally in the capsule format or enterically with the 
liquid suspension for those who are unable to take oral medications at the time of 
transplant. Patients should remain throughout the study within the tacrolimus C-0h blood 
trough levels as pre-specified in the trial protocol. The tacrolimus dose should be adjusted 
if tacrolimus C-0h blood trough levels are outside the required drug target range. In case 
of severe tacrolimus toxicity, dose reductions below the target levels may be performed 
at the investigator’s discretion.  If tacrolimus is interrupted for more than 21 consecutive 
days or cumulative for more than 28 days, discontinuation of study medication should be 
considered. In particular, interruptions for an elective medical treatment (e.g. dental 
treatments) are not to be counted. Tacrolimus may be interrupted during antibody 
treatment of rejection episodes or elective surgery.  
 
Mycophenolate mofetil 
MMF will be administered either orally in the capsule format or enterically with the liquid 
suspension for those who are unable to take oral medications at the time of transplant. 
Patients should be administered and remain on MMF per institutional protocol.  Dosage 
adjustments will be made based upon clinical practice/standard of care (SOC).  
Specifically, in subject randomized to group 2 (delayed everolimus), mycophenolate will 
be minimized as clinically indicated  

 
Basiliximab Preparation and Administration 
The 20mg dose of basiliximab will be given per labeled indication on day 0 and POD 4.  It will be 
diluted in 50mL of sterile 0.9% sodium chloride and may be administered via central or peripheral 
line over 20 to 30 minutes 
 
Rescue medication - Handling of acute rejection 
In all suspected acute rejection episodes, regardless of initiation of anti-rejection 
treatment, a graft core biopsy will be performed preferably within 24 hours, latest within 
48 hours, if clinically possible. Whenever possible, anti-rejection therapy should be 
postponed until a histological diagnosis of rejection is confirmed. 
 
Acute rejections will be treated with bolus methylprednisolone (other corticosteroids are 
acceptable at an equivalent dose) according to local practice.  
 
Other anti-rejection therapies (i.e. antibody therapy) should only be used in cases of 
steroid resistant rejections, or severe rejections with rejection activity index ≥7, or rare 
events of vascular rejection.  A biopsy-proven acute rejection occurring >14 days after the 
last day of the course of antirejection therapy given for the previous episode will be 
counted as a distinct event. 
 
Concomitant medications 
Investigator will be diligent and avoid administrating therapy with drugs that potentiate 
tacrolimus-related nephrotoxicity. 
 
In particular, the use of the following treatments is NOT allowed: 
- 
Other investigational drugs and non-protocol specified immunosuppressant drugs. 
- 
Drugs or substances that are strong inhibitors or inducers of CYP3A4.  Certain 
drugs may need to be used if no alternative treatment is available. In such cases, 
everolimus should be interrupted for the duration of the treatment. 
- 
If clinically significant proteinuria or nephrotic range proteinuria (protein-to-
creatinine ratio ≥500 mg/m2/24 hrs) occurs throughout the duration of the study, 
introduction of an angiotensin converting enzyme inhibitor or angiotensin receptor 
blocker should be considered as per local practice. 

 
Cytomegalovirus (CMV) prophylaxis 
Cytomegalovirus (CMV) prophylaxis will be administered according to local practice.  
 
Pneumocystis pneumonia (PJP) prophylaxis 
Prophylactic treatment for pneumocystis jiroveci pneumonia (PJP) consisting Bactrim® 
or equivalent (trimethoprim /sulfamethoxazole), starting when oral medication can be 
tolerated will be used as per local practice. Atovaquone or dapsone will be administered 
to patients unable to tolerate trimethoprim/sulfamethoxazole as per local practice. 
 
Fungal Prophylaxis/Treatment 
All patients will receive fungal prophylaxis and treatment according to local standard of 
care. Use of moderate inhibitors such as fluconazole will be permitted. 
 
If the systemic use of a strongly interacting drug is required, study medication can be 
temporarily interrupted (or permanently discontinued). 
 
Hepatitis B (HBV) prophylaxis 
Prophylaxis for recurrent hepatitis B during the course of this study will be per institutional 
protocol. 
 
Hepatitis C (HCV) treatment 
Treatment for HCV disease can be done but not preemptively. Investigators treat HCV 
only when recurrent HCV disease has been documented, based on histological evidence 
as determined by the local pathologist. Therapies used for post-baseline HCV disease 
will be appropriately documented. 
 
Lipid lowering medications 
During the course of the study, the lipid profile will be monitored. Lipid lowering 
medications should be administered according to guidelines and local practice. 

HMG CoA reductase inhibitors (e.g., pravastatin) will be administered according to local 
practice for the management of hyperlipidemia. Patients requiring treatment with this 
class of medication (especially lovastatin) should be monitored closely for signs of 
rhabdomyolysis, such as, dark-colored urine, fever, muscle cramps, pain, spasm, or 
stiffness, unusual tiredness or weakness. Lipid lowering therapy will be optimized before 
dosage reduction of study medication is considered. 
 
Contraception 
There are no adequate data from the use of everolimus in pregnant women. Studies in 
animals have shown reproductive toxicity effects including embryotoxicity and fetotoxicity. 
The potential risk for humans is unknown. Everolimus did not show genotoxicity in in vitro 
tests for gene mutations (bacteria and mammalian cells), and in an in vitro test and an in 
vivo mouse micronucleus assay for clastogenic activity. Therefore, male contraception is 
not indicated. 
 
Other concomitant medication 
Concomitant use of medications with a strong effect on CYP3A4 must be avoided, 
because of the risk for over- or under-exposure to everolimus. Investigators will instruct 
the subject to notify the study site about any new medications he/she takes after the start 
of the study medications.  
 
 
Prohibited treatment 
Uses of immunosuppressive agents such as azathioprine, sirolimus, and induction 
therapy with ALG, ATG, alemtuzumab or anti-tuberculosis agent as rifampin, and growth 
hormone therapy will not be allowed throughout the study. 
 
Discontinuation of study treatment and premature patient withdrawal 
Study treatment discontinuation 
The investigators will discontinue study medication for a given patient or withdraw the 
patient from study if, on balance, he/she believes that continuation would be detrimental 
to the patient’s well-being. In the absence of medical contraindication or significant 
protocol violation, every effort will be made to continue the patient on study medication 

 
Reasons for study drug discontinuation include: 
- 
Death. 
- 
Graft loss and/or re-transplantation. 
- 
Pregnancy 
- 
Withdrawal of consent. 
- 
Emergence of any serious adverse event (at the discretion of the investigator). 
- 
Unsatisfactory therapeutic effect (e.g. repeated acute rejection). 
- 
Administration of prohibited immunosuppressive medication. 
- 
Abnormal laboratory value(s) not resolved after study treatment interruption for 
more than 21 consecutive days or more than 2 episodes longer than 10 days, 
everolimus C-0h blood trough level ≥3 ng/mL cannot be maintained due to toxicity. 
- 
Abnormal test procedure result(s). 
- 
Significant protocol violation. 
- 
Any other protocol deviation that results in a significant risk to the patient’s safety. 
- 
Lost to follow-up. 
 
 
Efficacy 
Liver biopsy for suspected acute rejection 
Liver biopsies will be performed in all cases of suspected acute rejection preferably within 
24 hours and latest within 48 hours, whenever clinically possible. Whenever it is possible, 
anti-rejection therapy should be postponed until a local histological diagnosis of rejection 
is confirmed. The liver biopsy will be read by the pathologist according to the Banff 
classification of liver allograft rejection and will be used for patient management and 
treatment. 
 
 
Acute rejection 
All clinical suspected acute rejection episodes will be documented with the histological 
and clinical diagnosis specified.  
 
Treated acute rejection is defined as a clinically suspected acute rejection whether biopsy 
proven or not, which has been treated and confirmed by the investigator according to the 
response to therapy.   
 

Biopsy proven acute rejection and treated biopsy proven acute rejection 
A biopsy proven acute rejection (BPAR) is defined as clinically suspected acute rejection 
confirmed by biopsy.  In all suspected acute rejection episodes, regardless of initiation of 
anti-rejection treatment, a graft core biopsy will be performed preferably within 24 hours, 
latest within 48 hours whenever clinically possible. Whenever it is possible, anti-rejection 
therapy should be postponed until a local histological diagnosis of rejection is confirmed. 
The liver biopsies will be read by the pathologist according to the Banff classification of 
liver allograft rejection.  The local histo-pathology results will be used for patient treatment 
and management. A treated biopsy proven acute rejection (tBPAR) will be considered as 
efficacy event if the local pathologist reading with a RAI score ≥3 of acute rejection index 
was applied and consecutive anti-rejection therapy was administered to the patient. 
These readings will be used to assess the efficacy endpoint at Months 3 and 5 after the 
start of everolimus based regimen. 
 
Safety 
Renal function 
Serum creatinine, blood urea nitrogen, and serum cystatin C will be measured at all study 
visits and will be used to estimate the glomerular filtration rate by C/G (MDRD) 
 
Statistical analysis  
TBD 
 
Projected Enrollment Period 
March 22, 2019 through December 31, 2020 
 
Patient Population 
In a 2:2:1 scheme, 90 patients will be randomized at UCLA Medical Center between 
March 22, 2019 through December 31, 2020.  Each patient will be followed for six months 
post-transplant. 
 
Treatment Procedures 

One of the investigators will obtain written informed consent for this study from all patients 
or their legal representative (LAR) prior to the performance of any protocol procedure. 
Should any patient who previously had surrogate consent provided by their LAR regain 
their capacity to provide consent on their own, we will collect consent directly from that 
patient.  Per customary UCLA clinical practice, medical history will be taken, physical 
exam performed and labs drawn prior to transplant.  
 
 
 
DRUG THERAPY  
Group 1 
Basiliximab  
o Dose #1: 20mg IV within 2 hours of transplant  
o Dose #2: 20mg IV Post-operative day #4 
 
Tacrolimus (with basiliximab induction) 
o Beginning day #5 post-transplant or when SCr < 1.8 mg/dl (subjects off 
dialysis) to six months: 0.03-0.1mg/kg q12h PO to maintain whole blood 
trough concentration of 4-6ng/mL 
Mycophenolate mofetil 
o 500 mg po bid 
 
Corticosteroids (SOC):  Per UCLA protocol 
Post-operative taper: 
o Post-op day 1- 
methylprednisolone 50mg IVP Q6H 
o Post-op day 2- 
methylprednisolone 40mg IVP Q6H 
o Post-op day 3- 
methylprednisolone 30mg IVP Q6H 
o Post-op day 4- 
methylprednisolone 20mg IVP Q6H 
o Post-op day 5- 
methylprednisolone 20mg IVP Q12H 
o Post-op day 6- 
methylprednisolone 10mg IVP Q12H 
until taking PO, then change to:  prednisone 20mg PO QAM 
 
Group 2 
Basiliximab  
o Dose #1: 20mg IV within 2 hours of transplant  

o Dose #2: 20mg IV Post-operative day #4 
 
Tacrolimus (with basiliximab induction) 
o Beginning day #5 post-transplant or when SCr < 1.8 mg/dl (subjects off 
dialysis) to POD 30: 0.03-0.1mg/kg q12h PO to maintain whole blood 
trough concentration of 4-6ng/mL 
o POD 31; reduce to tacrolimus to 2-5ng/mL in presence of everolimus levels 
3-8 ng/mL 
 
Mycophenolate mofetil 
o 500 mg po bid up to POD 30:  reduce mycophenolate mofetil following 
achievement of steady state everolimus (POD 35) as clinically indicated 
 
Corticosteroids (SOC):  Per UCLA protocol 
Post-operative taper: 
o Post-op day 1- 
methylprednisolone 50mg IVP Q6H 
o Post-op day 2- 
methylprednisolone 40mg IVP Q6H 
o Post-op day 3- 
methylprednisolone 30mg IVP Q6H 
o Post-op day 4- 
methylprednisolone 20mg IVP Q6H 
o Post-op day 5- 
methylprednisolone 20mg IVP Q12H 
o Post-op day 6- 
methylprednisolone 10mg IVP Q12H  
until taking PO, then change to:  prednisone 20mg PO QAM 
 
Everolimus (delayed) 
o Add by POD 30: 1 mg po bid and adjusted to maintain whole blood trough 
concentrations of 3-8 ng/ml. 
 
Group 3 (control): 
Tacrolimus (without basiliximab induction) 
o Beginning day #1 post-transplant to six months: 0.03-0.1mg/kg q12h PO to 
maintain whole blood trough concentration of 5-12ng/mL 
o Six months to one year: maintain whole blood trough concentration of 5-
10ng/mL 
 
Mycophenolate mofetil 

o 500 mg po bid 
 
Corticosteroids (SOC):  Per UCLA protocol 
Post-operative taper: 
o Post-op day 1- 
methylprednisolone 50mg IVP Q6H 
o Post-op day 2- 
methylprednisolone 40mg IVP Q6H 
o Post-op day 3- 
methylprednisolone 30mg IVP Q6H 
o Post-op day 4- 
methylprednisolone 20mg IVP Q6H 
o Post-op day 5- 
methylprednisolone 20mg IVP Q12H 
o Post-op day 6- 
methylprednisolone 10mg IVP Q12H  
until taking PO, then change to:  prednisone 20mg PO QAM 
 
Calcineurin Inhibitor Rescue Therapy 
• If after 1 episode of acute rejection, full dose tacrolimus or cyclosporine may be 
used per UCLA liver transplant protocol. 
 
Infectious disease  
• Prophylaxis and treatment of all infectious diseases will be per UCLA liver 
transplant protocol 
 
Basiliximab Preparation and Administration 
The 20mg dose of basiliximab will be diluted in 50mL of sterile 0.9% sodium chloride and 
may be administered via central or peripheral line over 20 to 30 minutes.  
 
Gently invert the bag to avoid foaming.  Once the infusion is prepared, it should be 
administered IV within four hours.  Basiliximab is stable for up to 24 hours at 2-8oC.  
Infusion of basiliximab must be permanently terminated if the patient develops signs or 
symptoms suggestive of a severe allergic reaction 
 
 
 
Acute Rejection Assessments and Procedures 

• All patients with an unexplained deterioration in liver function (changes in total 
bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline 
phosphatase, or -glutamyltransferase concentrations) or the appearance of 
clinical signs of rejection (fever, jaundice, pruritis, ascites, or hepatic tenderness) 
will receive a liver biopsy 
• Treatment of acute rejection per standard clinical practice at UCLA 
 
 
Definition of Rejection 
The pathology department will classify any liver acute rejection episode per routine UCLA 
protocol. 
 
Evaluation of CD25 cell count 
• 5cc of blood will be drawn from the patient each day post-transplant until hospital 
discharge 
• 5cc of blood will be drawn at each post-transplant clinic visit 
• Monitoring of CD25 cell counts will take place over first 3 months post-transplant 
 
Adverse Events 
An adverse event is any adverse change from the patient's pre-treatment condition, which 
occurs during the course of the clinical trial, whether considered related to the treatment 
or not.  Clinical adverse event will be graded on a 3 point scale (mild, moderate, severe) 
by the following definitions 
1. mild- discomfort noticed, but no disruption of normal daily activity 
2. moderate- discomfort sufficient to decrease or affect normal daily activity 
3. severe- incapacitating - inability to work or perform normal daily activity 
 
Adverse events will be monitored in the hospital and at clinic visits. 
 
Criteria for Early Withdrawal 
All patients have the right to discontinue the clinical trial at any time for any reason.  
However, all patients who have discontinued the trial will be followed for the entire 6 
months post-transplant. 
Collection of Data 

Data on each enrolled patient will be kept on site at UCLA in a secured site.  Subject 
privacy and confidentiality will be maintained.  A computer generated database (coded 
encrypted data with access code) will maintain the files on each patient enrolled. 
 
Study Completion 
At study completion, results will be targeted towards the American Society of 
Transplantation and/or the journal American Journal of Transplantation, Liver 
Transplantation, or Transplantation 
 
Institutional Review Board/Ethics Committee 
This protocol and any other material provided to the patient will be provided to the 
Institutional Review Board/Ethics Committee.  Approval from the IRB/EC must be 
obtained before initiation of this clinical trial and should be documented in writing.  Any 
modifications made to the protocol must be submitted to the Committee. 
 
Estimated Budget 
~$3,500/patient 
 
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