Conditions: Kidney Failure
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 4
Healthy volunteers: no

Brief 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. 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.

Arms:
arm 1: Tacrolimus as maintenance immunosuppression arm 2: Everolimus as maintenance immunosuppression

Interventions: intervention 1: Tacrolimus intervention 2: Everolimus
Intervention descriptions: intervention 1: Low dose Tacrolimus intervention 2: Everolimus

Protocol document:
Prot_SAP_000.pdf: 
Version Date:  10/30/19 
 
Page 1 of 9 
 
Preservation of renal function after liver transplant for patients with pre-existing 
chronic kidney disease or peri-operative acute kidney injury using Everolimus plus 
mycophenolic acid immunosuppression regimen. 
 
Principal Investigator 
Chandrashekhar Kubal, MD, PhD 
Surgical Director, Liver Transplant Program (adult) Indiana University, School of Medicine 
IU Health University Hospital 
550 North University Boulevard 
Indianapolis, IN 46202 
 
 
1.0 Background 
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. 
Our liver transplant patients receive potent induction immunosuppression in the form 
of rabbit anti thymocyte globulin. We 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. 
 
2.0 Rationale and Specific Aims 
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 mycophenolic acid (Cellcept or Myfortic) in prevention of rejection is unknown.  
 
Primary Aim 
Assess the effect of Everolimus with or without mycophenolic acid versus Tacrolimus 
plus mycophenolic acid therapy on renal function measured by Glomerular Filtration 
Rate (GFR).  
 
Secondary Aims 
Compare the efficacy of Everolimus plus mycophenolic acid versus Tacrolimus plus 
mycophenolic acid therapy as measured by the following: 
• Biopsy-confirmed acute rejection  
• Hyperlipidemia 
• Proteinuria 


Version Date:  10/30/19 
 
Page 2 of 9 
 
• NODAT [New Onset Diabetes mellitus After Transplant], hypertension and 
malignancy 
 
 
3.0 Study Plan, Experimental Design, and Methodology 
The proposed investigation will be a single-center, randomized, open-label, active 
control comparison of the standard renal dysfunction maintenance immunosuppression 
regimen of reduced-dose Tacrolimus plus mycophenolic acid (control arm) versus 
Everolimus in combination with mycophenolic acid (study arm).  
 
4.0 Inclusion/Exclusion Criteria 
List Inclusion criteria:  
• 
Liver transplant recipients ≥ 18 years old 
• 
Renal dysfunction (GFR ≤ 60 mL/min) at 30 days post-operatively +/-7 days 
• 
Rabbit anti-thymocyte globulin (rATG) induction (at least 1 dose) 
• 
Indication for transplant: ethanol, hepatitis C, or nonalcoholic steatohepatitis 
 
List Exclusion criteria: 
• 
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 
 
 
5.0 Enrollment/Randomization 
Following transplant, prior to the one month post-transplant visit, all eligible subjects 
will be approached either in the transplant unit in the hospital or at the transplant clinic 
in the hospital for study participation.  A random permuted block design will be used to 
generate random assignments to the groups. This method will ensure balance across the 
groups over the course of the study period. The biostatistician at the Center for 
Outcomes Research in Surgery will prepare the master randomization assignment list. 
Clinical research coordinator will then administer randomization. Since this is an open 
label study, care providers will not be blinded to the randomization. We do not believe 
this will interfere with the results of the study or patient care.  
 


Version Date:  10/30/19 
 
Page 3 of 9 
 
Following enrollment, subjects will be randomized at one month post transplant to 
reduced dose Tacrolimus plus mycophenolic acid (control group) or to Everolimus plus 
mycophenolic acid (study group) maintenance immunosuppression. 
 
A previous Phase III study (Baboolal, 2003) showed that the mean creatinine clearance 
rate – a measure to assess the kidney function post-transplant – in the treatment group 
(those receiving Sirolimus and a CNI (Cyclosporine or Tacrolimus) with planned 
withdrawal of the CNI) was 65mL/min (SD=14) and in the control group (those who 
continued to receiving Sirolimus and a CNI) it was 57mL/min (SD=13). Therefore, using 
the two independent-groups and two-tail t-tests, we will need to recruit 46 patients in 
each group. With an attrition rate of 11% (Baboolal, 2003), we approximately need 104 
participants in this study (52 subjects in each arm) to achieve a statistical power of 80% 
at 0.05 level of significance. Power analysis and sample size calculation were done using 
G*Power 3.1.9.2. 
 
6.0 Study Procedures 
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 they are 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 
 
 
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 5 ± 1 ng/mL) plus 
mycophenolic acid (Cellcept or Myfortic). 
 
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 mycophenolic acid (Cellcept or Myfortic) therapy. 
mycophenolic acid dose as deemed appropriate per standard of care. Everolimus will be 
initiated at 1mg BID. Tacrolimus will be discontinued once Everolimus level is within goal 


Version Date:  10/30/19 
 
Page 4 of 9 
 
range, or at the discretion of the provider. The control arm will be maintained on the 
low dose Tacrolimus plus mycophenolic acid therapy.  
 
At 3 months, patients with GFR ≤60 will proceed to reduced dose Everolimus (target 
trough levels 3-6 ng/mL) plus mycophenolic acid therapy. Patients with GFR >60 will 
proceed to Everolimus monotherapy (target trough levels 4-8 ng/mL). 
 
If deemed clinically appropriate, mycophenolic acid may be held for up to 2 weeks. 
 
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, ERCP, biopsy as needed by clinical situation as SOC.   
 
 
7.0 Data to be Collected 
Target Population: Liver-only transplant patients 
 
Baseline Information: Demographics (age, race, sex, BMI), pre-treatment medical 
history, pre-treatment concomitant medication.    
 
Intervention: The treatment period starts at 30 days post transplant. Subjects will be 
followed for up to a total of 36 months post transplant. 
 
During the treatment period relevant concomitant medications, adverse events, 
complete blood counts, liver function panels, and immunosuppression drug levels will 
be collected. 
    
Follow-up: Data will be collected at 6 month, 12 month, 24 month, and 36 month 
timepoints. GFR will be measured at these time points. Any biopsy confirmed rejection 
that occurs on or before the 36 month timepoint will be recorded.  See Table 1 for 
timeline for data collection.   
 
Occurrence or change in NODAT [New Onset Diabetes mellitus After Transplant], 
neurocognitive function, hypertension, malignancy, and tolerance will be recorded 
throughout the length of the study. Results of any ultrasound, ECRP, or biopsy 
performed for clinical reasons will be recorded throughout the study. 
 
Study follow up will be conducted per standard of care. Patients will not undergo any 
additional visits for study purposes during treatment or follow up. 
 
 
 
 


Version Date:  10/30/19 
 
Page 5 of 9 
 
 
 
Table 1 
  
days 
Months 
  
0 1 7 
14 
21 
301 21 31 41 51 61 91 
122 
182 
242 
362 
Sr Creatinine 
x x x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Creatinine  Clearance x x x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
MDRD GFR 
x x x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Sr Glucose 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urine Protein 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Lipid profile 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
BP 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
LFT 
x x x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Everolimus level 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Tacrolimus level 
  
x x x 
x 
x 
# 
# 
# 
# 
# 
# 
# 
# 
# 
# 
# control patients 
1. +/- 7 days 
2. +/- 1 month 
 
8.0 Drug Information 
 
Please see the “CellCept_PM_E,” “Myfortic,” “Prograf-Tacrolimus,” and the “Zortress 
Package Insert” attachments. 
 
9.0 Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others 
 
Definitions of Adverse Events 
 
Adverse Event (AE) 
 
An adverse event is defined as untoward medical occurrence associated with the 
use of a drug or procedure in humans, whether or not considered drug or 
procedure related. An adverse event can be ANY unfavorable and unintended 
sign, symptom, or disease temporarily associated with the use of a medicinal 
(investigational) product or procedure, whether or not considered related to the 
medicinal (investigational) product or procedure (attribution of ‘unrelated’, 
‘unlikely’, ‘possible’, ‘probable’, or ‘definite’).  Examples of Adverse Events that 
will be recorded in this study are: 
 
• Concomitant illness 
• Physical injury 
• Events possibly related to medication 


Version Date:  10/30/19 
 
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• Significant worsening (change in nature, severity, or frequency) of the 
disease under study or other pre-existing conditions 
• Drug interactions 
• A laboratory or diagnostic test abnormality occurring shortly after the 
start of the study that results in the withdrawal of the patient from the 
study, requires medical treatment or further diagnostic work-up, or is 
considered by the study investigator to be clinically significant 
 
Adverse events will be graded according to the NCI Common Toxicity Criteria, 
Version 4.0.   
 
Serious Adverse Event (SAE) 
 
A serious adverse event is any untoward medical occurrence resulting in one or 
more of the following: 
 
• 
Results in death or ANY death occurring within 28 days of last dose of 
study drug (even if it is not felt to be drug related)  
• 
Is life-threatening (defined as an event in which the patient was at risk of 
death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe) 
• 
Requires inpatient hospitalization or prolongation of existing 
hospitalization 
NOTE: Hospitalizations that are not considered SAEs are:  
 Hospitalization for elective treatment of a pre-existing condition 
unrelated to study participation 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Is an important medical event (defined as a medical event(s) that may 
not be immediately life-threatening or result in death or hospitalization 
but, based upon appropriate medical and scientific judgment, may 
jeopardize the patient or may require intervention (e.g., medical, 
surgical) to prevent one of the other serious outcomes listed in the 
definition above).  Examples of such events include, but are not limited 
to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions not resulting in 
hospitalization; or the development of drug dependency or drug abuse. 
 
 
Unexpected Adverse Event 
 
An adverse event not mentioned in the package insert or the specificity or 
severity of which is not consistent with the package insert. 


Version Date:  10/30/19 
 
Page 7 of 9 
 
 
Determining Attribution to the Investigational Agent(s) 
 
Attribution: An assessment of the relationship between the AE and the medical 
intervention. CTCAE does not define an AE as necessarily “caused by a 
therapeutic intervention”. After naming and grading the event, the clinical 
investigator must assign an attribution to the AE using the following attribution 
categories: 
 
Relationship 
Attribution 
Description 
Unrelated to 
investigational 
agent/intervention 
Unrelated 
The AE is clearly NOT related 
Unlikely 
The AE is doubtfully related 
Related to investigational 
agent/intervention 
Possible 
The AE may be related 
Probable 
The AE is likely related 
Definite 
The AE is clearly related 
 
Adverse Event (AE) Reporting 
 
Adverse events (AEs) will be reported to the principal investigator immediately 
and will be recorded from the time of randomization (approximately 30 days 
after surgery), regardless of whether or not the event(s) are considered related 
to trial procedures or medications.  All AEs considered related to trial medication 
will be followed until resolution, return to baseline, or deemed clinically 
insignificant, even if this occurs post-trial. 
 
Reporting to the IRB:  
1. Unanticipated problems involving risks to subjects or others will be reported 
promptly to the IRB if they:  
1. were unexpected;  
2. were related or possibly related to study participation; AND  
3. suggests that the research places subject(s) or others at greater risk 
of harm than was previously known. 
 
If the serious adverse event does not meet all three (3) criteria listed above, the 
event does not have to be promptly reported to the Indiana University IRB.   
 
2. Prompt reporting of unanticipated problems to the IRB is defined as within 5 
business days of the study team becoming aware of the event. 
 
 
10.0 
Study Withdrawal/Discontinuation 


Version Date:  10/30/19 
 
Page 8 of 9 
 
Subjects may withdraw from the trial at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator for any reason.  If the patient 
withdraws from the trial and also withdraws consent for disclosure of future 
information, no further evaluations should be performed and no additional data should 
be collected. The investigator may retain and continue to use any data collected before 
such withdrawal of consent.  
  
 
11.0 Statistical Considerations 
 
Univariate analysis will be done to describe the distribution of the sample in terms of 
demographics (age, race, sex, BMI), pre-treatment medical history, pre-treatment 
concomitant medication. The distribution of the sample will be reported in terms of 
mean (±SD), median (Inter-quartile range), or percentage depending upon the type of 
variable (continuous or categorical). Bivariate analysis comparing the sociodemographic 
variables of the treatment groups will be conducted using chi squared, student T tests, 
Mann U Whitney, and ANOVA followed by Tukey’s pairwise comparison of the means as 
appropriate.  
 
Intent-to-treat analysis of the data from the baseline and follow-up visits will be 
analyzed in order to compare the renal functions after liver transplant between the 
study arm (those receiving Everolimus + mycophenolic acid)  and the control arm (those 
maintained on the low dose Tacrolimus monotherapy + mycophenolic acid therapy. 
Repeated measures analysis will be conducted to analyze measures of renal function 
after liver transplant across the treatment groups using multivariable generalized linear 
model (GLM) over time accounting for the correlation of the measurements obtained 
for each patient over time. For the secondary end-points, bivariate analysis will be done 
to compare the outcomes between the treatment and the control groups. Pearson’s chi-
square, student T tests, and Mann U Whitney tests as appropriate. Adjustment for the 
correlated variance due to repeated measures will be made throughout the analysis. All 
analysis will be conducted at 0.05 level of significance using Stata/SE version 14.2 
(StataCorp., 2015). 
12.0 Data Management 
Primary Data will be collected directly from the Electronic Medical Record databases 
CERNER, OTTR, and UNOS.  Records requests from third party hospitals will be collected 
as needed primarily for, but not limited to, Adverse Event reporting and medical history. 
Adverse Events will be recorded on paper CRFs. Each Adverse Event will be reviewed 
and attributed by the PI. The Adverse Event CRFs will be signed by the PI. Any lab values, 
drug levels, or other data not recorded in the Electronic Medical Record will be recorded 
by study personnel on paper CRFs and signed. 
 
Signed consents and HIPAA authorizations will be stored in study binders. Paper copies 
of record requests, paper CRFs, and any Notes To File will also be stored in these study 


Version Date:  10/30/19 
 
Page 9 of 9 
 
binders. Source material from the Electronic Medical Record will be printed only if 
needed for data quality control checks and stored in the study binders. Study binders 
will be stored in a HIPAA compliant, locked room.  
 
Data will be stored electronically in REDCap. The REDCap data file will be backed up 
manually at least every month on a separate, HIPAA-compliant IU Box Health folder. The 
database will be built and tested by a biostatistician prior to the production mode. 
 
Data collected in the electronic database will undergo random audits to ensure 
accuracy. A data safety officer (Dr. Asif Sharfuddin from Department of Medicine, 
Division of Nephrology will kindly serve as the data safety officer and will perform 
quality control checks on the entered data. 
 
 
13.0 Follow-up and Record Retention 
Subjects will be followed for up to a total of 36 months following transplant.  All records 
produced or collected in connection with this research project, including primary (e.g., 
laboratory, medical), financial, statistical, supporting, administrative, and regulatory 
documentation, shall be retained for a minimum period of seven (7) years. 
 
References: 
1. 
P De Simone, F Nevens, L De Carlis, et al (2012) “Everolimus With Reduced 
Tacrolimus Improves Renal Function in De Novo Liver Transplant Recipients: A 
Randomized Controlled Trial” Am J Transplant. 2012 Nov; 12(11): 3008–3020. doi:  
10.1111/j.1600-6143.2012.04212.x 
2. 
Saliba F, De Simone P, Nevens F et al  (2013) Renal function at two years in liver  
transplant patients receiving everolimus: results of a randomized, multicenter study. 
Am J Transplant. 2013 Jul;13(7):1734-45.  
3. 
Fischer L, Saliba F, Kaiser GM et al (2015) Three-year Outcomes in De Novo Liver  
transplant Patients Receiving Everolimus With Reduced Tacrolimus: Follow-Up Results  
From a Randomized, Multicenter Study. Transplantation. 2015 Jul;99(7):1455-62. 
 
4. 
Li L1, Wozniak LJ, Rodder S, Heish S, et al. (2012) A common peripheral blood  
gene set for diagnosis of operational tolerance in pediatric and adult liver transplantation. 
Am J Transplant. 2012; 12(5):1218-28