Clinical trial NCT02974686
Conditions: Kidney Transplant Rejection Gastrointestinal Disorder, Functional
Sponsor: Washington University School of Medicine
Start date: 2016-11-01; Completion date: 2019-09-01
Enrollment: 1 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Patients who receive renal transplantation at Barnes Jewish Hospital (BJH) are placed on triple maintenance immunosuppression, which means that patients take 3 types of immunosuppression drugs to suppress their immune system including tacrolimus, mycophenolate (MPA), and prednisone. However, due to the effects of MPA on the gastrointestinal tract, patients often complain of GI adverse effects. Current practice is to either dose-reduce MPA or convert the patient to an alternative agent, typically Azathioprine. Both of these strategies have limitations, largely due to concerns related to efficacy. Everolimus (EVR) has demonstrated similar efficacy to MPA in renal transplantation and may offer a benefit related to GI adverse effects, so the investigators will convert patients to EVR in this study. Patients who are within their first year post-transplant will be converted to EVR upon enrollment in the study, and serial measurements ,or a series of measurements looking for an increase or decrease over time, of GI adverse effects will be conducted over 1 year post-enrollment.

Detailed description:

Arms: arm 1: Patients experiencing gastrointestinal adverse effects in the first year post transplant will be converted from mycophenolate to everolimus arm 2: Patient will have baseline data collected while on MPA for comparison with EVR
Interventions: intervention 1: Everolimus intervention 2: Mycophenolic Acid
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
Conversion from MPA to Zortress (Everolimus) for GI toxicity post-renal transplant 
 
NCT number: 02974686 
 
 
 
Trial was terminated with only 1 participant enrolled. No data is reported here to maintain patient 
confidentiality. 
 
 


 
EVEROLIMUS 
Clinical Study Protocol CRAD001AUS209T 
Conversion from MPA to Zortress (everolimus) for GI toxicity 
post-renal transplantation 
Authors: 
Delos Santos, R, Hagopian, J 
Principle or Coordinating 
Investigator 
Delos Santos, R 
Document type: 
Clinical Study Protocol 
Version number: 
02  
Release date: 
031-May-2018 


Table of contents 
Table of contents .................................................................................................. 3 
List of tables .......................................................................................................... 5 
List of figures......................................................................................................... 5 
List of abbreviations .............................................................................................. 6 
Glossary of terms .................................................................................................. 7 
Protocol synopsis .................................................................................................. 8 
1 
Background ......................................................................................................... 10 
2 
Purpose and rationale ......................................................................................... 10 
3 
Objectives ........................................................................................................... 11 
3.1 
Primary objectives .................................................................................... 11 
3.2 
Secondary objectives ............................................................................... 11 
3.3 
Exploratory objectives ................................ Error! Bookmark not defined. 
4 
Study design ....................................................................................................... 11 
5 
Population ........................................................................................................... 12 
5.1 
Inclusion criteria ....................................................................................... 12 
5.2 
Exclusion criteria ...................................................................................... 13 
6 
Treatment ........................................................................................................... 13 
6.1 
Investigational and control drugs .............................................................. 13 
6.2 
Treatment arms ........................................................................................ 13 
6.3 
Treatment assignment .............................................................................. 13 
6.4 
Treatment blinding .................................................................................... 13 
6.5 
Treating the patient .................................................................................. 13 
6.5.1 
Patient numbering ..................................................................... 13 
6.5.2 
Dispensing the study drug ......................................................... 14 
6.5.3 
Study drug supply, storage and tracking.................................... 14 
6.5.4 
Instructions for prescribing and taking the study drug ............... 14 
6.5.5 
Permitted study drug dose adjustments and interruptions ......... 14 
6.5.6 
Rescue medication ...................... Error! Bookmark not defined. 
6.5.7 
Other concomitant treatment ..................................................... 14 
6.5.8 
Study drug discontinuation and premature patient withdrawalError! 
Bookmark not defined. 
6.5.9 
Emergency unblinding of treatment assignment Error! Bookmark 
not defined. 
6.5.10 
Study completion and post-study treatment Error! Bookmark not 
defined. 
6.5.11 
Early study termination ................ Error! Bookmark not defined. 
7 
Visit schedule and assessments ......................................................................... 14 


7.1 
Information to be collected on screening failures ...... Error! Bookmark not 
defined. 
7.2 
Patient demographics/other baseline characteristics ............................... 15 
7.3 
Treatment exposure and compliance ....................................................... 16 
7.4 
Efficacy ..................................................................................................... 16 
7.4.1 
Efficacy assessment 1 ................. Error! Bookmark not defined. 
7.4.2 
Appropriateness of efficacy measurements Error! Bookmark not 
defined. 
7.5 
Safety ....................................................................................................... 16 
7.5.1 
Physical examination ................................................................. 17 
7.5.2 
Vital signs .................................................................................. 17 
7.5.3 
Height and weight ...................................................................... 17 
7.5.4 
Laboratory evaluations .............................................................. 17 
7.5.5 
Electrocardiogram (ECG) ............ Error! Bookmark not defined. 
7.5.6 
Pregnancy and assessments of fertility ..................................... 17 
7.5.7 
Appropriateness of safety measurements .. Error! Bookmark not 
defined. 
7.6 
Other assessments .................................................................................. 17 
7.6.1 
Health-related Quality of Life ..................................................... 17 
7.6.2 
Pharmacokinetics ........................ Error! Bookmark not defined. 
7.6.3 
Pharmacogenetics/pharmacogenomics ...... Error! Bookmark not 
defined. 
7.6.4 
Other biomarkers ......................... Error! Bookmark not defined. 
8 
Safety monitoring ................................................................................................ 18 
8.1 
Adverse events ......................................................................................... 18 
8.2 
Serious adverse event reporting ............................................................... 18 
8.3 
Pregnancies ............................................................................................. 19 
9 
Data review and database management ............................................................ 19 
9.1 
Data collection .......................................................................................... 19 
9.2 
Database management and quality control .............................................. 19 
10 Data analysis (Any or all sections may be included based on type of study) ...... 19 
10.1 Populations for analysis............................................................................ 19 
10.2 Patient demographics/other baseline characteristics ............................... 19 
10.3 Treatments (study drug, rescue medication, other concomitant therapies, 
compliance) .............................................................................................. 19 
10.4 Analysis of the primary objective(s) .......................................................... 20 
10.4.1 
Variable ..................................................................................... 20 
10.4.2 
Statistical hypothesis, model, and method of analysis ............... 20 


10.4.3 
Handling of missing values/censoring/discontinuations ............. 20 
10.4.4 
Supportive analyses .................................................................. 20 
10.5 Analysis of secondary objectives .............................................................. 20 
10.5.1 
Efficacy (secondary) .................................................................. 20 
10.5.2 
Safety ........................................................................................ 20 
10.5.3 
Resource utilization ..................... Error! Bookmark not defined. 
10.5.4 
Health-related Quality of Life ..................................................... 20 
10.5.5 
Pharmacokinetics ........................ Error! Bookmark not defined. 
10.5.6 
Pharmacogenetics/pharmacogenomics ...... Error! Bookmark not 
defined. 
10.5.7 
Biomarkers .................................. Error! Bookmark not defined. 
10.5.8 
PK/PD .......................................... Error! Bookmark not defined. 
10.6 Sample size calculation ............................................................................ 20 
10.7 Power for analysis of critical secondary variables ..... Error! Bookmark not 
defined. 
10.8 Interim analysis .......................................... Error! Bookmark not defined. 
11 Ethical considerations ......................................................................................... 21 
11.1 Regulatory and ethical compliance ........................................................... 21 
11.2 Informed consent procedures ................................................................... 21 
11.3 Responsibilities of the investigator and IRB/IEC/REB .............................. 21 
11.4 Publication of study protocol and results .................................................. 21 
12 Protocol adherence ............................................................................................. 22 
12.1 Protocol Amendments .............................................................................. 22 
13 References.......................................................................................................... 22 
 
List of tables 
Table 7-1 
Assessment schedule ................................................................ 15 
 
List of figures 
Figure 4-1 
Study design .............................................................................. 12 
 


List of abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
b.i.d. 
twice a day 
CRF 
Case Report/Record Form 
CRD 
Clinical Research and Development 
CPO 
Country Pharma Organization 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
ECG 
Electrocardiogram 
EC-MPS 
Enteric-coated mycophenolate sodium 
EVR 
Everolimus 
ICH 
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IMS 
Integrated Medical Safety 
i.v. 
intravenous(ly) 
IRB 
Institutional Review Board 
IVRS 
Interactive Voice Response System  
MMF 
Mycophenolate mofetil 
MPA 
Mycophenolic 
acid 
(Refers 
to 
mycophenolate 
sodium 
EC 
or 
mycophenolate mofetil containing products) 
o.d. 
once a day 
p.o. 
oral(ly) 
REB 
Research Ethics Board 
SAE 
serious adverse event 


Glossary of terms 
 
Assessment 
A procedure used to generate data required by the study 
Control drug 
A study drug used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study 
validity, and/or evaluate comparative effects of the investigational 
drug 
Enrollment 
Point/time of patient entry into the study; the point at which 
informed consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol) 
Investigational drug 
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug.” 
Medication number 
A unique identifier on the label of each medication package in 
studies that dispense medication using an IVR system 
Patient number 
A number assigned to each patient who enrolls in the study. When 
combined with the center number, a unique identifier is created for 
each patient in the study. 
Stage 
A major subdivision of the study timeline; begins and ends with 
major study milestones such as enrollment,, completion of 
treatment, etc. 
Period 
A minor subdivision of the study timeline; divides phases into 
smaller functional segments such as screening, baseline, titration, 
washout, etc. 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the 
planned completion of all study drug administration and 
assessments; at this time all study drug administration is 
discontinued and no further assessments are planned 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or 
when study drug was discontinued whichever is later 
Study drug 
Any drug administered to the patient as part of the required study 
procedures; includes investigational drug and any control drugs 
Study drug discontinuation 
Point/time when patient permanently stops taking study drug for 
any reason; may or may not also be the point/time of premature 
patient withdrawal 
Variable 
Information used in the data analysis; derived directly or indirectly 
from data collected using specified assessments at specified 
timepoints 
 


Protocol synopsis 
Title of study: Conversion from MPA to Zortress (everolimus) for GI toxicity post-renal transplantation 
This study is a prospective, single-center study to evaluate the effectiveness of conversion from MMF or 
EC-MPS to EVR during the first year post-renal transplant in patients who experience gastrointestinal 
adverse effects.  The primary outcome will be change in GSRS from baseline (time of conversion) to 30 
days post-conversion.  
In total, 25 patients will be enrolled and converted from MPA to EVR, at an initial dose of 1 mg PO BID with 
target everolimus troughs between 3 – 8 ng/mL. Patients who are less than one year from date of transplant 
with identified GI symptoms who are on immunosuppression with tacrolimus, MPA, and prednisone will be 
enrolled and followed for 1 year. These patients will be compared to an historical cohort of patients receiving 
azathioprine for safety outcomes (including rejection and graft/patient survival). 
Purpose and rationale: Cellcept® (mycophenolate mofetil, MMF) and Myfortic® (enteric-coated 
mycophenolate sodium, EC-MPS) are the two formulations of mycophenolic acid (MPA) approved for use 
as adjunctive immunosuppression post-renal transplantation.  Non-infectious gastrointestinal (GI) adverse 
effects are the main dose-limiting toxicity of MPA therapy, which has been reported in up to 45% of MPA-
treated patients. MPA dose reductions, treatment interruptions, discontinuations or withdrawals are 
common due to GI toxicity from these agents.  Studies have demonstrated that patients with GI 
complications who experienced an MMF dose adjustment or discontinuation had a significantly increased 
incidence of acute rejections compared with patients without GI complications (30.2% vs. 19.4%, p=0.005). 
At Barnes-Jewish Hospital/Washington University School of Medicine in St. Louis, it is standard practice to 
place patients on triple maintenance immunosuppression therapy with MMF or EC-MPS, tacrolimus, and 
prednisone immediately post-renal transplantation.  Patients may be switched from MMF or EC-MPS to 
azathioprine due to GI symptoms.  We feel that everolimus may offer a similar advantage to azathioprine 
for patients unable to tolerate MMF or EC-MPS in regard to similar incidence of acute rejection, low 
incidence of GI-related adverse effects, and other patient-oriented outcomes.     
Objectives:  
Primary objective: To determine if a switch from MMF or EC-MPS to Zortress (everolimus) due to GI   
 
intolerance results in improvement of GI symptoms.  
Secondary objectives:  To determine whether it is safe to switch from MMF or EC-MPS to Zortress 
(everolimus) due to GI intolerance from MMF/EC-MPS within 12 months post-renal transplantation. 
Population:  
The population will include adult recipients of living- or deceased-donor renal allografts within the previous 
12 months at Washington University/Barnes-Jewish Hospital who are on tacrolimus and prednisone and 
are experiencing GI toxicity from MPA and have stable renal function with a GFR > 35 mL/min. 
 
Inclusion/Exclusion criteria:   
Key inclusion criteria  
1. Kidney transplant recipients at Washington University/Barnes-Jewish Hospital 
2. Experiencing GI toxicity from MPA as determined by the treating physician within 12 months 
post-renal transplant 
3. On standard immunosuppression with tacrolimus and prednisone 
 
Key exclusion criteria 
1. Dual organ or kidney after another solid organ transplant 
2. Presence of a preexisting significant GI condition that does not have a presumed causal 
relationship with MPA  


3. Evidence of any GI disorder induced by an infection, underlying medical condition, or 
concomitant medication other than MPA 
4. eGFR<35 ml/min at time of possible conversion 
5. Proteinuria >1 gram/day at time of possible conversion 
6. Profound bone marrow suppression at the time of possible conversion as defined as: 
 
Hemoglobin <10 g/dL 
 
WBC <3 K/cumm 
 
Platelets <100 K/cumm 
7. Wound healing issues at time of possible conversion (eg, wound dehiscence, wound infection, 
incisional hernia, lymphocele, seroma) 
8. Elevated total cholesterol (>350 mg/dL) and/or triglycerides (>500 ng/dL) at time of possible 
conversion 
9. Hypersensitivity to everolimus, sirolimus, or other rapamycin deriviatives 
Investigational and reference therapy:  
Investigational therapy 
- 
Everolimus tablets 0.25 mg, 0.5 mg, and/or 0.75 mg  
Study design: Patients will be selected if they experience non-infectious GI adverse effects within the first 
12 months post transplant. Following selection they will have a baseline screening and enrollment with a 
complete medical history, medication history, vital signs and labs (including tacrolimus and everolimus 
levels). In addition, their adverse effects and GSRS and GIQLI will be recorded. After enrollment they will 
have medication history, vitals, labs (including tacrolimus and everolimus), and GSRS/GIQLI and adverse 
events recorded at months 1, 3, 6, 9, and 12 (excepting GSRS and GIQLI at month 9). 
Efficacy assessments:  
- 
Change in GSRS from baseline to month 3 
- 
Change in GSRS subscores from baseline to month 3 
- 
Changes in GSRS from basline to month 6 and 12   
- 
Change in GIQLI from baseline to month 3 
- 
Change in GIQLI subscores from baseline to month 3 
- 
Changes in GIQLI from baseline to month 6 and 12 
Other assessments:  
- 
BPAR rates during study (compared with historical control) 
- 
eGFR by MDRD4 from baseline to month 12 (compared to historical control) 
- 
Death (compared with historical control) 
- 
Graft loss (compared with historical control) 
Data analysis:  
Data for primary  and secondary efficacy will be compared using a paired T-test. 
 


Background 
Cellcept® (mycophenolate mofetil, MMF) and Myfortic® (enteric-coated mycophenolate sodium, EC-MPS) 
are the two formulations of mycophenolic acid (MPA) approved for use as adjunctive immunosuppression 
post-renal transplantation.  Non-infectious gastrointestinal (GI) adverse effects are the main dose-limiting 
toxicity of MPA therapy, which has been reported in up to 45% of MPA-treated patients. MPA dose 
reductions, treatment interruptions, discontinuations or withdrawals are common due to GI toxicity from 
these agents.  Studies have demonstrated that patients with GI complications who experienced an MMF 
dose adjustment or discontinuation had a significantly increased incidence of acute rejections compared 
with patients without GI complications (30.2% vs. 19.4%, p=0.005). At Barnes-Jewish Hospital/Washington 
University School of Medicine in St. Louis, it is standard practice to place patients on triple maintenance 
immunosuppression therapy with MMF or EC-MPS, tacrolimus, and prednisone immediately post-renal 
transplantation.  Patients may be switched from MMF or EC-MPS to azathioprine due to GI symptoms.  We 
feel that everolimus (EVR) may offer a similar advantage to azathioprine for patients unable to tolerate 
MMF or EC-MPS in regard to similar incidence of acute rejection, low incidence of GI-related adverse 
effects, and other patient-oriented outcomes.     
Purpose and rationale 
This study is a prospective, single-center, single-arm study to evaluate the effectiveness of conversion from 
MMF or EC-MPS to EVR during the first year post-renal transplant in patients who experience 
gastrointestinal adverse effects.  The secondary outcomes will include a comparison of EVR-based 
immunosuppression to azathioprine (AZA)-based immunosuppression, which is the current standard of 
practice at this institution. It is felt that EVR-based immunosuppression may offer certain advantages over 
AZA, including the ability to use lower-exposure tacrolimus maintenance and preserve kidney function as 
compared to AZA or MPA.  
Management of GI adverse effects following kidney transplantation has been established as a consistent 
challenge for transplant centers. Reduction of MPA immunosuppression may lead to adverse outcomes 
such as rejection or graft failure, and use of AZA has been associated with higher rates of graft loss. 
Everolimus has been studied in kidney transplant recipients, and has been shown to lead to similar rates 
of rejection and graft function compared to MPA. Thus, we have proposed this single-arm study to assess 
improvement in GI adverse effects in renal transplant recipients. If EVR demonstrates a significant benefit 
with regard to GI adverse effects while maintaining appropriate rejection prophylaxis, it may offer transplant 
a new option for patients who are experiencing such adverse effects while on MPA therapy. 
We will assess patients within the first year post-transplant for signs and symptoms of GI adverse effects, 
and following ruling out infectious causes, they will be consented and converted to EVR at an initial dose 
of 1 mg PO BID, which will then be titrated to target trough goals between 3 – 8 ng/mL. Prior to drug 
initiation, patients will complete the GSRS and GIQLI surveys to assess for intensity of symptoms and 
associated quality of life. Patients will remain on study therapy for at least 12 months and GSRS and GIQLI 
will be repeated at 30 days, 3 months, 6 months, and 12 months.  
These timelines were chosen to allow enough time to demonstrate a significant change in GSRS scores 
following conversion to EVR. We have chosen not to include an active control due to the added cost and 
time that would be required to enroll and follow the additional numbers needed. We will compare data on 
graft rejection, graft function, graft survival, and patient survival to an historic cohort of patients who were 
converted to AZA for GI adverse effects. They will be compared on a 2:1 basis to a group of randomly 
selected patients previously converted to AZA. 


Objectives 
Primary objectives  
To determine if a switch from MMF or EC-MPS to Zortress (everolimus) due to GI  intolerance results in 
improvement of GI symptoms, as measured with the GSRS survey. 
Secondary objectives 
To determine whether it is safe to switch from MMF or EC-MPS to Zortress (everolimus) due to GI 
intolerance from MMF/EC-MPS within 12 months post-renal transplantation. 
Study design 
This study will be conducted over a 2-year period, during which patients will be enrolled through the first 
year, and follow-up of a minimum of 1 year will be collected on each patient. Interim analyses will be 
conducted at 6-months or upon enrollment of 15 patients (whichever is earliest). The interim analyses will 
assess the rate of study drug discontinuation due to non-efficacy (as determined by nephrologist). If more 
than 5 patients (33%) have discontinued drug due to non-efficacy, the study will be terminated. Additionally, 
any other problems or safety signals will be addressed by the research team at this time. 
Subjects meeting criteria will be asked to sign an informed consent, and upon execution of informed consent 
this will be considered study day 1.  They will examined on study day 1 including a medical history, 
medication history, vital signs, height, weight, and BMI. Subjects will complete GSRS and GIQLI surveys, 
report adverse effects, and complete laboratory tests, including tacrolimus levels. Subjects will have 5 
additional visits during the study period, which will include a medication history, vital signs, 
height/weight/BMI, adverse effect recording, GSRS and GIQLI (excepting visit 5), laboratory work including 
tacrolimus and everolimus levels, and reporting of infectious symptoms. These visits will occur at the end 
of months 1, 3, 6, 9, and 12. 


Figure Error! No text of specified style in document.-1 
Study design 
 
Population 
We intend to include patients who have received kidney transplant at the Washington University/Barnes-
Jewish Hospital transplant program in the year prior to enrollment who are exhibiting signs of non-infectious 
GI toxicity determined by the treating physician to be secondary to MPA. In total, 30 candidates will be 
enrolled and treated with conversion from MPA to EVR. We anticipate a dropout rate of 20%, and expect 
that 24 patients will complete a full year of study drug. Severity of GI adverse effects will be assessed using 
the GSRS and GIQLI scales, but no specific severity threshold will be used to enroll patients. The study will 
be conducted largely on outpatients, but patients may be initially enrolled during inpatient stays. 
Inclusion criteria 
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 
1. 
Patients must give written informed consent before any assessment is performed. 
2. 
Adult kidney transplant recipients at Washington University/Barnes-Jewish Hospital 
3. 
Experiencing GI toxicity from MPA as determined by the treating physician within 12 months post-
renal transplant 
4. 
On standard immunosuppression with tacrolimus and prednisone 
Day 1: 
Screening: 
- History/Physical 
- Baseline assessments (GSRS 
and GIQLI) 
- Baseline labs 
- Drug levels (Tac only) 
Month 1 (end of month): 
Follow-up visit 
- Vitals, Ht/Wt/BMI 
- Medication history 
- Adverse events 
- GSRS and GIQLI 
- Labs and drug levels 
- Evidence of infections 
Month 3 (end of month): 
Follow-up visit 
- Vitals, Ht/Wt/BMI 
- Medication history 
- Adverse events 
- GSRS and GIQLI 
- Labs and drug levels 
- Evidence of infections 
Month 6 (end of month): 
Follow-up visit 
- Vitals, Ht/Wt/BMI 
- Medication history 
- Adverse events 
- GSRS and GIQLI 
- Labs and drug levels 
- Evidence of infections 
Month 9 (end of month): 
Follow-up visit 
- Vitals, Ht/Wt/BMI 
- Medication history 
- Adverse events 
- Labs and drug levels 
- Evidence of infections 
Month 12(end of month) 
Follow-up visit 
- Vitals, Ht/Wt/BMI 
- Medication history 
- Adverse events 
- GSRS and GIQLI 
- Labs and drug levels 
- Evidence of infections 
Day 1: 
Medication 
dispensed 
Day 365


Exclusion criteria 
1. 
Dual organ or kidney after another solid organ transplant 
2. 
Presence of a preexisting significant GI condition that does not have a presumed causal 
relationship with MPA  
3. 
Evidence of any GI disorder induced by an infection, underlying medical condition, or concomitant 
medication other than MPA 
4. 
eGFR<35 ml/min at time of possible conversion 
5. 
Proteinuria >1 gram/day at time of possible conversion 
6. 
Profound bone marrow suppression at the time of possible conversion as defined as: 
• 
Hemoglobin <10 g/dL 
• 
WBC <3 K/cumm 
• 
Platelets <100 K/cumm 
7. 
Wound healing issues at time of possible conversion (eg, wound dehiscence, wound infection, 
incisional hernia, lymphocele, seroma) 
8. 
Elevated total cholesterol (>350 mg/dL) and/or triglycerides (>500 ng/dL) at time of possible 
conversion 
9. 
Hypersensitivity to everolimus, sirolimus, or other rapamycin deriviatives 
Treatment 
Investigational and control drugs 
Patients enrolled in the trial will receive everolimus tablets at a starting dose of 1 mg PO BID, which will be 
dispensed in 0.5 mg tablets in blister-packages of 60-each.  
Treatment arms 
This will be a single-arm study. All patients enrolled with be assigned to the everolimus arm. We will include 
an observational retrospective analysis of those on AZA-based immunosuppression for comparison of risk 
of acute rejection, chronic rejection, graft-loss, and death, but these patients have already been allocated 
treatment and completed follow-up. 
Treatment assignment 
This will be a single-arm study. All patients enrolled with be assigned to the everolimus arm. 
Treatment blinding 
This will be an open-label study. All participants including researchers, subjects, and analysts will be aware 
of treatment allocation. 
Treating the patient  
Patient numbering 
Patients will be numbered sequentially from 1 through 30 based on the order they complete consent and 
enrol in the study 


Dispensing the study drug 
Study drug will be dispensed by the Barnes-Jewish Hospital Investigational New Drug (BJH IND) pharmacy, 
216 S. Kingshighway Blvd. They will receive a supply of 360 tablets of the 0.5 mg strength during their first 
study visit with a prescription label as outlined below.  
Study drug supply, storage and tracking 
Study drug supply with be shipped to the IND pharmacy, and it will be stored within an automated 
dispensing cabinet system (PYXIS), accessible only to the BJH IND pharmacy staff. Dispensing logs will 
be maintained by the BJH IND pharmacy staff, and the study team will track doses assigned for each patient 
during and following the titration period. 
Instructions for prescribing and taking the study drug 
Upon enrollment, patients will be instructed to begin taking 2 tablets by mouth twice daily beginning the 
evening following enrollment. Patients will continue taking everolimus twice daily through the study duration 
until the morning of the final visit (visit 6- end of month 12). The dose will be adjusted based on everolimus 
trough levels (as measured in whole blood using liquid chromatography and mass spectrophotometry 
methods) to target an everolimus level between 3 and 8 ng/mL. These assessments of everolimus levels 
will be made on a q2week schedule initially. 
Permitted study drug dose adjustments and interruptions 
As above, patients will have regular assessments of their everolimus levels. The first level assessment will 
be taken no sooner than 3 days following administration of the first dose. Any dose changes will lead to 
follow-up levels no sooner than 3 days following dose adjustment. The trough goal for EVR for the study is 
between 3 and 8 ng/mL. Levels below 3 ng/mL should result in a dose adjustment equaling double the 
previous dose. Levels above 8 ng/mL should result in a decrease in dose by 0.25 mg per dose. Changes 
to dose may also be made at treating physician discretion.  
 
Additionally, tacrolimus levels will be assessed and doses adjusted upon these levels, targeting a trough 
level between 2 and 5 ng/mL. Adjustments to TAC doses may be made at treating physician discretion.  
Drug interruptions may occur at the discretion of treating physician for severe or opportunistic infection, 
evidence of adverse effects requiring interruption (such as pulmonary infiltrates), or during periods of severe 
illness where oral route is unavailable. 
Other concomitant treatment 
Stong inducers or inhibitors of CYP3A4/3A5 are prohibited. 
Visit schedule and assessments 
Table 7-1 lists all of the assessments and indicates with an “x” the visits when they are performed. The 
day of enrollment will be considered to be study Day 1. Subjects will make scheduled study visits on Day 
1, at the end of Months 1, 3, 6, and 12. Subjects who discontinue their study treatment regimen should be 
treated according to standard of care immunosuppression and return for the assessments indicated by X 
in Table 6-1. If they refuse to return for these assessments or are unable to do so, every effort should be 
made to contact them or a knowledgeable informant by telephone to determine the subject and graft 
status. 


Table Error! No text of specified style in document.-1 
Assessment schedule 
 
Screening 
And 
Enrollment 
Treatment period (post-switch) 
Final 
study visit 
Month 
1 
Month 
3 
Month 
6 
Month 
9 
Month 12 
Visit 
1 
2 
3 
4 
5 
6 
Medical history 
X 
 
 
 
 
 
Medication history  
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
Height, weight, BMI 
X 
X 
X 
X 
X 
X 
Informed consent 
X 
 
 
 
 
 
Dispense medication and/or 
instruct subject regarding use 
X 
 
 
 
 
 
Record adverse events 
X 
X 
X 
X 
X 
X 
GSRS and GIQLI instruments  
X 
X 
X 
X 
 
X 
Clinical laboratory tests 
X 
X 
X 
X 
X 
X 
Tacrolimus/everolimus trough 
levels 
**Trough concentrations to be 
drawn twice weekly upon 
initiation and/or dosage change 
until therapeutic goal level is 
obtained 
X 
X 
X 
X 
X 
X 
Evidence of bacterial, viral, and 
fungal infection 
**At the following visits and at 
any point such infection is 
reported to a physician, 
transplant coordinator, or study 
coordinator 
X 
X 
X 
X 
X 
X 
 
Patient demographics/other baseline characteristics 
After informed consent has been signed and the subject’s eligibility to participate in the study has been 
determined, baseline subject information will be obtained in accordance with local regulations, including 
date of birth, age, sex (with child bearing status for females), race and ethnicity. In addition, relevant 
medical history (including CKD and ESRD history) and current medical conditions at screening, a full 
physical examination, vital signs and a pregnancy test (for females of child-bearing potential) will also be 
performed (or documented if recently performed). At Baseline/Transplantation information on the renal 
transplant procedure, recipient and donor transplant background, recipient and donor viral serology and 
recipient/donor HLA testing results will be recorded. Post-transplant, when all Inclusion/Exclusion criteria 
are met, the subject may begin receiving drug.  
 


Treatment exposure and compliance 
All pre-transplant immunosuppression administered, such as basiliximab, rATG and any other agents (CNI, 
MPA and/or corticosteroids) administered pre-enrollment will be recorded. All post-enrollment doses of 
everolimus and tacrolimus administered during the course of the study will be recorded in the data 
monitoring sheets. For all these immunosuppressive drugs the start date, total dose, stop date and reason 
for dose administration or dose change are to be provided. Tacrolimus trough levels will be determined 
locally and recorded on the data monitoring sheets. The local trough values will be used to adjust the 
tacrolimus dosing. Everolimus trough levels will be determined by the local laboratory and recorded on the 
data monitoring sheets. 
Efficacy  
Gastrointestinal Symptom Rating Scale (GSRS) 
At each study visit, with the exception of study visit #5, the will be administered by a member of the study 
team. Subjects will be interviewed by one of the investigators, and their responses will be recorded at each 
time point. The interviewer will be provided a sheet with each of the symptom areas, the associated 
questions, and the rating scale to conduct the interview. They will ask each question and read each potential 
response to the patient and circle the associated answer. These scores will be used to calculate their overall 
GSRS score, as well as the 5 sub-scores. The GSRS has been validated in numerous studies, including 
the initial study of the GSRS (Svelund J. Dig Dis Sci. 1988) which demonstrated validity and strong interrater 
reliability. It has subsequently been studied in the setting of kidney transplant recipients experiencing non-
infectious GI adverse effects (Bolin P. Transplantation 2007). The scores in each of the domains 
(indigestion, diarrhea, constipation, abdominal pain, and reflux) will be recorded following the interview and 
will be compared longitudinally. 
Gatrointestinal Quality of Life Index (GIQLI) 
Following completion of the GSRS, the interviewer will then provide a paper copy of the GIQLI for the patient 
to complete. This is a 36-question survey containing 5 domains (Core symptoms, physical items, 
psychological items, social items, social items, and disease items) which each question contains 5 possible 
answers (which are rated from 0 – 4). Subjects will be asked to review the survey and each question, and 
circle the associated answer and return the survey to the interviewer. The interviewer will record the 
responses to each question and scores will be calculated and tracked for each patient longitudinally. The 
utility of this survey has been demonstrated by an initial assessment of reliability (Eypasch E. Br J Surgery. 
1995) and has been used in multiple studies to assess any gastrointestinal symptoms and has 
demonstrated reproducibility. 
Safety 
 
Treated Biopsy Proven Acute Rejection (tBPAR) 
A treated BPAR is any condition where the subject received anti-rejection treatment and was 
histologically diagnosed as acute rejection. Renal biopsies will be collected for all cases of suspected 
acute rejection. 
 
Kidney allograft biopsy 
For all suspected rejection episodes, regardless of initiation of anti-rejection treatment, an allograft biopsy 
must be performed within 48 hrs. Biopsies will be read by the pathologist according to the updated Banff 
2009 criteria. The results of the biopsy read by the pathologist will be recorded in the research database. 
The results will be used for subject management for acute rejection. The local pathologist will remain 
blinded to treatment. Any biopsies performed according to local practice (e.g. not for cause) should also 
be recorded. 
 
Graft Loss 


The allograft will be presumed to be lost on the day the subject starts dialysis and is not able to 
subsequently be removed from dialysis. If the subject undergoes allograft nephrectomy prior to starting 
permanent dialysis, then the day of nephrectomy is the day of graft loss. 
 
Death 
In the event of subject death, the SAE leading to Death should be reported to the sponsor DS&E within 
24 hr. 
 
Renal Function 
Renal function by calculated eGFR using the MDRD4 formula (Coresh, 2003) from enrollment to Month 
12 is a primary variable for assessment of renal function in this study. This will also be the primary 
method of assessment of renal function with respect to other renal endpoints. 
 
Physical examination 
A thorough physical assessment will be performed at Screening, Months 3, 6 and 12. Information about 
the physical examination will be recorded in the visit history document. Significant findings that are 
present prior to the start of the study must be included. 
Vital signs 
Vital signs (radial pulse rate and blood pressure) will be recorded at each study visit in the visit history 
document. Blood pressure and pulse rate will be assessed at the same arm each time of determination and 
after the subject has rested in the sitting position (may be supine if during hospitalization) for at least five 
minutes. Systolic and diastolic blood pressure will be measured three times using an automated validated 
device, e.g. OMRON, with an appropriately sized cuff. The repeat sitting measurements will be made at 1-
2 minute intervals and the mean of the three measurements will be recorded on the Vital Signs CRF. In 
case the cuff sizes available are not large enough for the subject's arm circumference, a 
sphygmomanometer with an appropriately sized cuff may be used. 
Height and weight 
Height will be recorded at Screening only, weight will be recorded at Screening and at each subsequent 
visit. Results will be recorded in the visit history form. 
Laboratory evaluations 
All lab work will be conducted at local laboratories, with the exception of study visit laboratories, which will 
be conducted on-site. 
Pregnancy and assessments of fertility 
Pregnancy testing (serum) must be carried out for all females of child-bearing potential. A negative serum 
pregnancy test must be recorded within 30 days of enrollment. 
Other assessments 
As above 
Health-related Quality of Life 
As above 


Safety monitoring 
Adverse events 
Definition of an AE: Any untoward medical occurrence in a subject administered a pharmaceutical product 
that does not necessarily have a causal relationship with the treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not considered 
related to the investigational medicinal product. 
Investigational Medicinal Product (IMP) includes the drug under evaluation and the comparator drug(s) if 
specified as part of the research objective, given at any time during the study. Medical conditions/diseases 
present before starting the drug of interest are only considered adverse events if they worsen after starting 
the drug of interest. 
The occurrence of adverse events will be sought by non-directive questioning of the patient at each visit 
during the study. Adverse events also may be detected when they are volunteered by the patient during or 
between visits or through physical examination, laboratory test, or other assessments. All adverse events 
will be recorded in the study database including the following information: 
1. 
the severity grade (mild, moderate, severe) or (grade 1-4) (delete 1 of the 2 options) 
2. 
its relationship to the drug(s) of interest (suspected/not suspected) 
3. 
its duration (start and end dates or if continuing at final exam) 
4. 
whether it constitutes a serious adverse event (SAE) 
Serious adverse event reporting 
A SAE is any untoward medical occurrence that at any dose: 
- 
results in death, 
- 
is life-threatening, 
- 
requires inpatient hospitalization or prolongation of existing hospitalization, 
- 
results in persistent or significant disability/incapacity, 
- 
is a congenital anomaly/birth defect,  
- 
is otherwise a significant medical event. 
This includes any SAEs likely to arise from the trial indication or progression of underlying/concomitant 
illness (es) (e.g. progression of cancer in oncology trials), unless specified in the protocol as study specific 
exemptions. 
Any SAE, irrespective of causality, occurring after the subject has provided informed consent and until four 
weeks after the subject has stopped study participation must be reported unless otherwise stated in the 
protocol. SAEs occurring after four weeks from ending study participation should only be reported if 
considered by the Investigator attributable to the exposure to the investigational drug(s) during the trial 
period. This includes the period in which the study protocol interferes with the standard medical treatment 
given to a subject, even if study treatment has not yet started (e.g. withdrawal of previous treatment during 
washout period, change in treatment to a fixed dose of concomitant medication). 
 
Timelines: All serious adverse events (SAEs) from interventional clinical trials must be reported by the sites 
to Sponsor within 24 hours of occurrence of the SAE. The timelines for investigator initiated trials reporting 
to the sponsor will be done as per Third Party Study/Investigator Initiated Trial Agreement.   
Follow-up reports:  


SAEs will be followed until resolution or until it is judged to be permanent, and an assessment will be made 
at each visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
drug of interest, the interventions required to treat it, and the outcome.  
The Sponsor shall support  in the following-up of all SAEs so that complete information is available to 
maintain patient safety and also as part of any commitments by the sponsor to any Health authority OR 
specific Health authority follow-up requests for the product under investigation. 
Pregnancies 
To ensure patient safety, each pregnancy in a patient (or a patients partner) on study drug must be reported 
to the sponsor within 24 hours of learning of its occurrence. The pregnancy will be followed up to determine 
outcome, including spontaneous or voluntary termination, details of the birth, and the presence or absence 
of any birth defects, congenital abnormalities, or maternal and/or newborn complications. 
Data review and database management 
Data collection 
Data collection will occur via the RedCap system. All local staff have received training on RedCap. Multiple 
forms will be created, including a baseline/screening form, and visit-specific forms. Only investigators will 
have access and the ability to download data.  
Database management and quality control 
The principal investigator will take responsibility for assessing quality data entry by overseeing all data entry 
into the RedCap system. 
Data analysis (Any or all sections may be included based on type of 
study) 
Statistical analysis and report writing will be performed when the last subject has completed 12 months on 
study.  
Populations for analysis 
Subjects completing three months of therapy and returning for study visit #2 will be included in the primary 
analysis. All subjects receiving at least one dose of everolimus will be included in all outcomes related to 
safety. 
Patient demographics/other baseline characteristics 
Demographic and background information for the population will be summarized using frequency 
distribution (for categorical variables) and descriptive statistics of mean, median, maximum, minimum and 
standard deviation (for continuous variables). 
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance) 
The number of patients remaining on study medication at each study visit will be recorded. 
Additionally, mean tacrolimus and everolimus levels will be reported at each study visit. 


Analysis of the primary objective(s) 
Variable 
The primary variable is the resultant score derived from the GSRS, which ranges from 0 – 45, compared at 
enrollment and at visit 2 (end of month 3). 
Statistical hypothesis, model, and method of analysis 
The null hypothesis: Conversion from MPA-based immunosuppression to EVR-based immunosuppression 
will result in similar GSRS scores at 3 months compared to baseline. 
We will analyze changes in the GSRS using a paired T-test. 
Handling of missing values/censoring/discontinuations 
We will not include patients in the primary analysis and subsequent analyses of efficacy if they drop out of 
the study. We will analyze safety endpoints from a modified ITT approach, whereby patients receiving at 
least one dose of everolimus are considered on therapy until the end of their study period (12 months). 
Supportive analyses 
A per-protocol set will be analyzed as a secondary endpoint with regards to safety endpoints, including 
BPAR, graft loss, and death. 
Analysis of secondary objectives 
Efficacy (secondary) 
We will conduct analysis of GIQLI scores at visit 2, 3, 4, and 6 compared with baseline assessment, as well 
as inter-visit comparisons. Additionally, we will conduct subscore analyses of the GSRS and GIQLI at each 
of these timepoints. The pre-specified domains of the GSRS to be analyzed will be the abdominal pain, 
diarrhea and reflux scores. The GIQLI subscores will be analyzed for all domains. 
Safety 
Safety variables to be assessed include BPAR, graft loss, death, graft function at each study visit, 
discontinuation from study, discontinuation from treatment, infection, SAE, notable events, laboratory 
tests, and vital signs. All safety analyses will be done on the safety set. Selected variables will be 
analyzed using all available data including data assessed. 
Health-related Quality of Life 
As above. 
Sample size calculation 
- 
The sample size was calculated based on the myTIME study.  Sample size calculation showed that a 
minimum sample size of 25 patients will be required to provided 80% power to detect a change from 
baseline of 12 points in the total GSRS score (15-105 scale) considering a 0.05 significance level and 
a standard deviation of 18 and allowing for a 20% dropout.  A paired t test will be utilized to compare 
the overall GSRS score, the GSRS subscale scores, and the GIQLI from baseline.   


- 
Assuming a 5% 1-year rate of acute rejection, we plan to evaluate 60 historical control patients to 
compare differences in the secondary endpoints of acute rejection, graft survival, patient survival, and 
infections.  The historical control group will be randomly selected from a consecutive list of patients 
who received a renal transplant during the same study period and were maintained on MMF 500mg-
1gram BID or EC-MPS 360-720mg BID, tacrolimus, and prednisone and met stated inclusion and 
exclusion criteria as listed below.  30 conversion patients will be enrolled and compared 1:2 with 
historical controls.   
- 
Statistical analysis for the historical control comparison will utilize the Chi-squared test for events, 
ANOVA for renal function outcome differences and other continuous variables, and Kaplan-Meier 
estimates for patient and graft survival 
Ethical considerations 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance with the ICH 
Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations (including 
European Directive 2001/20/EC, US Code of Federal Regulations Title 21, and Japanese Ministry of Health, 
Labor, and Welfare), and with the ethical principles laid down in the Declaration of Helsinki. 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where required by law 
or regulation), IRB/IEC/REB-approved informed consent, or, if incapable of doing so, after such consent 
has been provided by a legally acceptable representative of the patient. In cases where the patient’s 
representative gives consent, the patient should be informed about the study to the extent possible given 
his/her understanding. If the patient is capable of doing so, he/she should indicate assent by personally 
signing and dating the written informed consent document or a separate assent form. Informed consent 
must be obtained before conducting any study-specific procedures (i.e. all of the procedures described in 
the protocol). The process of obtaining informed consent should be documented in the patient source 
documents.  
Women of child bearing potential should be informed that taking the study medication may involve unknown 
risks to the fetus if pregnancy were to occur during the study and agree that in order to participate in the 
study they must adhere to the contraception requirement for the duration of the study. If there is any 
question that the patient will not reliably comply, they should not be entered in the study. 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a properly 
constituted 
Institutional 
Review 
Board/Independent 
Ethics 
Committee/Research 
Ethics 
Board 
(IRB/IEC/REB) before study start. A signed and dated statement that the protocol and informed consent 
have been approved by the IRB/IEC/REB must be given to the sponsor before study initiation. 
Publication of study protocol and results 
Type here 


Protocol adherence 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that must be 
approved by the sponsor, Health Authorities where required, and the IRB/IEC/REB. Only amendments that 
are required for patient safety may be implemented prior to IRB/IEC/REB approval. Notwithstanding the 
need for approval of formal protocol amendments, the investigator is expected to take any immediate action 
required for the safety of any patient included in this study, even if this action represents a deviation from 
the protocol. 
References 
1. Behrend M. Adverse GI effects of mycophenolate mofetil: aetiology, incidence and management. Drug 
Saf 2001; 24:645.  
2. European Mycophenolate Mofetil Study Group. Placebocontrolled study of mycophenolate mofetil 
combined with cyclosporin and corticosteroids for prevention of acute 
rejection. Lancet 1995; 345:1321.  
3. Tierce JC, Porterfield-Baxa J, Petrilla AA, et al. Impact of mycophenolate mofietil (MMF)-related 
gastrointestinal complications and MMF dose alerations on transplant outcomes and healthcare costs in 
renal transplant recipients. Clin Transplant. 2005; 19(6):779.