Conditions: Kidney Failure
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 14
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 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.

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

Interventions: intervention 1: Tacrolimus intervention 2: Everolimus
Intervention descriptions: intervention 1: Tacrolimus (FK / Prograf) titrated to a goal trough of 6 - 8 ng/ml intervention 2: Everolimus monotherapy - target trough levels 4 - 8 ng/ml as maintenance immunosuppression

Protocol document:
Prot_SAP_001.pdf: 
Version Date:  11/26/19 
 
Page 1 of 9 
 
Protection of renal function after liver transplant using Everolimus monotherapy as 
the 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 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. [1-
3] In this trial we are proposing to advance this approach further by completely 
eliminating Tacrolimus from patients’ immunosuppression protocol. The rationale for 
this approach is based on our unique induction immunosuppression protocol.   
 
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. By completely eliminating Tacrolimus, we 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.  
 
2.0 Rationale and Specific Aims 
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).  
 
Secondary Aims 
Compare the efficacy and safety of Everolimus monotherapy versus Tacrolimus 
monotherapy, as measured by the following: 


Version Date:  11/26/19 
 
Page 2 of 9 
 
• Biopsy-confirmed acute rejection  
• Hyperlipidemia 
• Proteinuria 
• 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 tacrolimus as the maintenance immunosuppression (control arm) 
versus Everolimus (study arm).  
 
4.0 Inclusion/Exclusion Criteria 
List Inclusion criteria:  
• 
Liver transplant recipients ≥ 18 years old 
• 
Normal baseline renal function (GFR > 60 mL/min) 
• 
Rabbit anti-thymocyte globulin (rATG) induction (at least one dose) 
• 
Indication for transplant: ethanol, hepatitis C, nonalcoholic steatohepatitis or any  
combination of these 
 
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 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. 
 
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. 
The surgery 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:  11/26/19 
 
Page 3 of 9 
 
 
Following enrollment, subjects will be randomized at one month post-transplant to 
Tacrolimus (control) or to Everolimus (study) as 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: 
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 


Version Date:  11/26/19 
 
Page 4 of 9 
 
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, 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], 
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:  11/26/19 
 
Page 5 of 9 
 
Table 1 
 
 
Used for study only if available per patient standard of care. 
 
 
 
8.0 Drug Information 
 
Please see the “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: 
  
days 
Months +/- one week 
  
0 1 7 
14 
21 
30 
days 
2 
3 
4 5 6 9 
12 
18 
24 
36 
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 
Total Cholesterol 
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 


Version Date:  11/26/19 
 
Page 6 of 9 
 
 
• Concomitant illness 
• Physical injury 
• Events possibly related to medication 
• 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. 
 


Version Date:  11/26/19 
 
Page 7 of 9 
 
 
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. 
 
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.  
However, it will be reported at the time of continuing review. 


Version Date:  11/26/19 
 
Page 8 of 9 
 
 
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 
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 described 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 tests 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 + low dose Tacrolimus)  and the control arm 
(those maintained on the Tacrolimus monotherapy (target trough levels 6-8 ng/mL). 
Repeated measures analysis will be conducted to analyze measures of renal function 
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, 


Version Date:  11/26/19 
 
Page 9 of 9 
 
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 
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 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