Clinical trial NCT01935128
Conditions: Renal Transplant
Keywords: Renal Transplant Immunosuppression Steroid Avoidance Calcineurin Avoidance Mammalian Target of Rapamycin (mTOR) Kidney
Sponsor: University of Toledo Health Science Campus
Start date: 2013-07-03; Completion date: 2020-07-01
Enrollment: 55 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate whether conversion to everolimus (Zortress®), allowing the elimination or reduction of calcineurin inhibitors, will reduce nephrotoxicity (measured by increased creatinine clearance) and lengthen overall graft (kidney transplant) survival (measured by 2-3 year graft survival).

Detailed description:
The purpose of this study is to evaluate whether conversion to everolimus (Zortress®), allowing the elimination or reduction of calcineurin inhibitors, will reduce nephrotoxicity (measured by increased creatinine clearance) and lengthen overall graft (kidney transplant) survival (measured by 2-3 year graft survival). Among the worst of the long-term effects of chronic immunosuppression are the nephrotoxicity (toxic to kidney cells) of the calcineurin inhibitors and the myriad complications of steroids. This protocol evaluates the elimination or reduction of calcineurin inhibitors in a protocol that has already successfully eliminated the long-term use of steroids. A considerable need remains for safer therapeutic agents that inhibit T-cell activation (a white blood cell that attacks foreign cells as part of the immune response) via a calcineurin independent or reduced-dose mechanism of action.

Arms: arm 1: In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml.
Interventions: intervention 1: Arm 1 Everolimus/Reduced dose tacrolimus
Intervention descriptions: intervention 1: Immunosuppression drug intervention

Protocol documents:
Prot_SAP_000.pdf: 
 
                                   M. Rees        February 05, 2018 
1
 
 
 
 
 
 
A 24-month, single center, pilot, open label, controlled trial to evaluate 
the efficacy and safety of calcineurin-inhibitor reduction with 
conversion at 2 months to Reduced Dose tacrolimus/everolimus in adult 
renal transplant recipients following Campath® induction and steroid 
avoidance 
 
 
 
 
 
NCT01935128 
 
 
2/5/2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
                                   M. Rees        February 05, 2018 
2
A 24-month, single center, pilot, open label, controlled trial to evaluate 
the efficacy and safety of calcineurin-inhibitor reduction with 
conversion at 2 months to Reduced Dose tacrolimus/everolimus in adult 
renal transplant recipients following Campath® induction and steroid 
avoidance 
 
Introduction 
 
 
Campath-1H is a monoclonal antibody that was originally produced in a mouse 
against the human leukocyte antigen CD52.1 CD52, a cell surface protein (antigen), is 
present on all lymphocytes and most monocytes.  Campath-1H efficacy is related to its 
ability to cause profound depletion of T-lymphocytes long-term and B cell and monocyte 
depletion more transiently.  Campath-1H not only depletes the blood of these cells, but it 
also penetrates to the lymphatic system to cause depletion there as well.  Campath-1 was 
originally called Campath-1G (IgG2b) or Campath-1M (IgM) when it was a mouse 
antibody.  It was genetically engineered so that the constant region of the mouse antibody 
was replaced with the human equivalent and it was renamed Campath-1H.  Thus, 
Campath-1H only has mouse antibody segment at the binding site and the rest is of 
human origin; because of this, it is much less likely to elicit an anti-Campath® antibody 
response such as that which limits the re-use of OKT3® or Thymoglobulin®.  In 
addition, because Campath-1H does not bind directly to the T-cell receptor (like 
OKT3®), it is much less likely to cause a cytokine release syndrome with a subsequent 
first dose reaction. 
 
Background and Preliminary Data 
 
 
Campath® was first used in the early 1980s by Peter Friend at Addenbrooke’s 
Hospital at the University of Cambridge to treat acute rejection episodes of renal 
transplants.  He combined Campath® with full dose triple drug immunosuppression of 
cyclosporine, Imuran® and steroids.  Campath® was very effective at reversing rejection, 
but subsequently many of the treated patients died of overwhelming infections.  This 
result led to concerns that it was too powerful of an immunosuppressant agent and it was 
not used again until the late 1980s.  This time, instead of using Campath® for rejection, 
Peter Friend conducted a new trial using Campath® as an induction agent in renal 
transplantation.  It was given for 10 days post-operatively and patients were then treated 
with full dose triple drug immunosuppression of cyclosporine, Imuran® and steroids.2  
This protocol was very effective at preventing rejection, but again a significant number of 
patients developed life-threatening infections and the antibody was not used again for 
nearly another decade. 
 
In the late 1990s, Campath® was studied again in Cambridge under the leadership 
of Professor Sir Roy Calne.  Campath-1H was administered as just two doses as an 
induction agent.  The dose of Campath® was reduced, as was the intensity of post-
operative maintenance immunosuppression, given the earlier failures due to over-
immunosuppression.  The first dose of 20 mg was given immediately pre-or post-
operatively and the second dose of 20 mg was given about 1 day post-operatively.  
Patients were immunosuppressed intra-operatively and on post-op day 1 with high dose 


 
                                   M. Rees        February 05, 2018 
3
steroids, and then maintained only on half-dose cyclosporine to aim for a trough level of 
about 100 ng/ml.  After one year over 90% of the kidneys were still functioning and the 
rejection rate was lower than that in traditional triple drug immunosuppression.3-5  
Subsequently, the 5 year post-transplant follow-up of these 31 patients demonstrated a 
71% 5 year-graft survival, again better than would be expected for a contemporary group 
of patients treated with triple drug immunosuppression.6 
 
Other researchers explored the use of Campath® as an immunosuppressive agent 
for renal transplantation.  The first was Stuart Knechtle at the University of Wisconsin 
who combined Campath® with monotherapy Rapamune® instead of cyclosporine as was 
done in Cambridge.  Stuart Knechtle reasoned that Rapamune® rather than a calcineurin 
inhibitor such as cyclosporine might allow for tolerance mechanisms leading to graft 
acceptance following lymphocyte depletion (in fact, this work was funded by the Immune 
Tolerance Network).  This idea was based on work in mice that supported this concept.7  
Therefore, rather than using half-dose cyclosporine monotherapy as had been 
successfully done in the Cambridge trial, Knechtle tried using Rapamune® monotherapy 
post-operatively.  Campath® induction with 40 mg total dose was used in 29 primary 
human renal transplants and the patients were maintained on Rapamune® monotherapy 
(levels 8-15 ng/mL) post-transplantation.  They found that Campath® profoundly 
depleted T- lymphocytes long-term and more transiently depleted B cells and monocytes. 
Unfortunately, there was a high rejection rate (8 of 29, 28%) with this combination with 
many of the rejections being a humoral rejection (5 of 8, 63 %) and one of these resulting 
in a graft loss.8  All patients were alive and well after 3-29 months of follow up. One 
graft was lost because of rejection and seven of the 29 patients were converted to 
standard triple therapy on account of rejection. There were no systemic infections and no 
malignancies.  
 
Allan Kirk at the NIH used Campath-1H alone without any subsequent 
immunosuppression in an attempt to induce tolerance.  He did not see rejection for the 
first several weeks but then by the end of the first month or second month all the patients 
had rejections that were responsive to steroids and the initiation of Rapamune®.  
Interestingly, all of the rejections showed no evidence of lymphocytic infiltration on 
biopsy.  Instead, macrophages appeared to be responsible for the rejection.9  For this 
reason, Allan Kirk performed a follow-up study where he used deoxyspergualin as an 
anti-macrophage immunosuppressant post transplantation with Campath-1H induction.  
Unfortunately, this set of patients fared no better than the initial seven patients he had 
treated with Campath-1H alone.10 
 
Stuart Knechtle and the Wisconsin group continued to use Campath-1H as their 
induction agent.  After the questionable results with Campath-1H and monotherapy 
Rapamune®, they used Campath-1H in renal transplant recipients in combination with a 
calcineurin inhibitor, mycophenolate mofetil, and low-dose steroid therapy.11 They 
published results treating 126 consecutive renal allograft recipients with 2 doses of 
Campath-1H antibody on days 0 and 1. Patients treated with Campath-1H were compared 
with patients who received Simulect® (an anti-CD25 antibody, n=799), Thymoglobulin® 
(a rabbit anti-human thymus polyclonal antibody preparation, n=160), or other antibody 
treatment (n=156) in combination with a calcineurin inhibitor, mycophenolate mofetil, 
and higher dose steroids. The Campath-1H group overall experienced less rejection than 
the other 3 groups (P=.037). Patients with delayed graft function experienced less 


 
                                   M. Rees        February 05, 2018 
4
rejection with Campath-1H than control groups (P=.0096) and had improved graft 
survival (P=.0119). There was no difference in infection or malignancies between the 4 
groups. Overall, they found that Campath-1H was well tolerated in renal transplant 
patients and led to significant reductions in incidence of rejection.  In particular, they 
noted that patients with delayed graft function experienced significantly improved graft 
survival. 
 
In May 2001, Campath® was approved by the FDA for the treatment of B-cell 
lymphomas.12  It was to be used at a dose that was substantially higher than that which 
was necessary for renal transplantation induction.  However, now that the drug was 
commercially available, it was possible that it could be used off-label for renal 
transplantation induction. 
 
Dixon Kauffman and his colleagues at Northwestern University in Chicago were 
ready to take this approach.  In fact, they realized that using Campath-1H instead of 
Simulect® would reduce their cost of induction by half and, compared with 
Thymoglobulin® induction, they could reduce their cost by nearly 90%.  Thus, they 
replaced Thymoglobulin® with Campath® as their induction agent.  They had been 
doing steroid avoidance trials and felt they would be more successful if they had better 
initial lymphocyte depletion.13  They used a single-center, nonrandomized, retrospective, 
sequential study design to evaluate outcomes in kidney transplant recipients given either 
Campath® (n = 123) or Simulect® (n = 155) induction in combination with a prednisone-
free maintenance protocol using tacrolimus and mycophenolate mofetil. Overall long-
term patient and graft survival rates did not significantly differ between patients treated 
with Campath® and Simulect®.  A lower rate of early (<3 months) rejection was 
observed in the Campath® (4.1%) versus the Simulect® (11.6%) group, but the rates for 
both groups were equivalent at 1 year.  Patient and kidney survival and rejection rates 
were nearly identical between Caucasians and African Americans that received 
Campath®.  Quality of renal function and incidence of infectious complications were 
similar in the two groups. Campath® induction therapy was similar in efficacy to 
Simulect® in a prednisone-free maintenance immunosuppressive protocol for an 
ethnically diverse population of kidney transplant recipients.  This same group 
subsequently went on to show that Campath® was also safe to use in a steroid-free 
regimen in patients receiving simultaneous kidney and pancreas transplants.14  In 
communication with Dr. Kauffman in October 2006, Northwestern University had used 
Campath® induction to prevent rejection in over 1000 renal transplant recipients 
followed by Prograf® and Cellcept® with a subsequent overall rejection rate of 11% at 
one year (9 % in recipients of living donor kidneys and 13% in recipients of deceased 
donor kidneys).(personal communication, M. Rees) 
 
Peter Friend added another study to the Campath® story with a multi-center trial 
carried out in collaboration with Stuart Flechner at the Cleveland Clinic.15 They 
performed a pilot study in which 22 kidney recipients (14 LD: 8 DCD) were given 
Campath® induction (30 mg day 0 and 1), steroids (500 mg mp day 0 and 1, none 
thereafter), Cellcept® (MMF) maintenance (500 mg b.i.d) and sirolimus (concentration 
controlled 8-12 ng/mL). With a mean follow-up of 15.9 months, patient survival was 
(21/22) 96% and graft survival (19/22) 87%. Acute rejections occurred in (8) 36.3% (two 
humoral). Of 19 surviving grafts, 18 (95%) remained steroid and 15 (79%) CNI-free. At 
1 year, mean creatinine was 1.43 mg/dL. Overall infection rates were low, but 2 patients 


 
                                   M. Rees        February 05, 2018 
5
developed severe acute respiratory distress syndrome (ARDS) at month 3 and 7, 
respectively, resulting in mortality in one and a graft loss in the other. No cancer or 
PTLD was observed. Leukopenia was common and MMF dose was reduced or 
eliminated in 6/22 (27%) patients. The reported higher than expected rate of acute 
rejection, leukopenia and possible pulmonary toxicity suggested excessive morbidity and 
the authors suggested that modifications such as an initial period of CNI use should be 
considered. 
 
Another group to make an important contribution to the Campath® literature has 
been led by Ron Shapiro at the University of Pittsburgh and their protocol is explored in 
further detail as it served as the model for the initial use of Campath® at the University of 
Toledo (except of spaced weaning of Prograf®). Pittsburgh used Campath-1H as 
induction as only one dose on day zero.  The dose was 0.5 mg/kg for patients up to the 
weight of 60 kg.  Any patient whose weight is > 60 kg is given a total dose of 30 mg 
Campath-1H intravenously.  Recipients were pre-medicated with Tylenol® 650 mg PO, 
Benadryl® 25 mg IV, Pepcid® 20 mg IV and Methylprednisolone 1 gram IV.  A second 
dose of Methylprednisolone was given just before the arterial clamps were removed.  No 
further steroids were administered.  The patients were given monotherapy Prograf® post-
operatively aiming to keep the level at about 10 ng/ml for the first 4 months and then 
patients were slowly weaned to lower Prograf® doses with 62% of the patients being 
successfully weaned to every other day Prograf® dosing. 
            Pittsburgh has published several interval reports on their experience, but the most 
recent publication details their experience with Campath® pretreatment with tacrolimus 
monotherapy and subsequent spaced weaning in 200 consecutive live donor renal 
transplantations with a mean 3 years of follow-up.16 Outcomes were reported for patients 
receiving living donor renal transplantation between March 2003 and December 2005. 
The actuarial 1-, 2- and 3-year patient survivals were 99.0%, 96.4%, and 93.3%  while 
the graft survivals were and 98.0%, 90.8%, and 86.3%. The cumulative incidence of 
acute cellular rejection was 1.0% ≤ 1 month, 1.0% ≤ 3 months, 2.0% ≤ 6 months, 9.0% ≤ 
12 months, 16.5% ≤ 18 months, 19.5% ≤ 24 months, 23.5% ≤ 30 months, 24.0% ≤ 36 
months and 25% ≤ 42 months. Only 1.5% of the patient population experienced an 
incidence of acute cellular rejection beyond 2.5 years post-transplantation. Based on 
these results as well as data regarding the incidence of infection, chronic allograft 
nephropathy and other complications (CMV disease, posttransplant lymphoproliferative 
disorder and new onset insulin dependent diabetes mellitus posttransplant – only 1 out of 
144), the authors conclude that the outcomes confirm the safety and efficacy of this 
approach at 3 years post-transplantation. Patient and graft survival results equate to those 
of living donor renal transplant recipients in the database of the Scientific Registry of 
Transplant Recipients. 
 
Ciancio et al. from Miami added a cautionary note to the use of Campath® in 
African Americans, although the number of patients in their study was too small to 
demonstrate clear significance.17 In a retrospective study of the first 75 primary renal 
transplant patients given Campath® induction at the University of Miami, 20 were 
African American (27%), 32 were Hispanic (43%), and 23 were non-African American, 
non-Hispanic (31%). Immunosuppression consisted of Campath® given intraoperatively 
and 4 days later (0.3 mg/kg), with low-dose maintenance mycophenolate mofetil (500 mg 
twice daily) and tacrolimus (targeted trough levels of 5 to 7 ng/ml) and no corticosteroid 


 
                                   M. Rees        February 05, 2018 
6
therapy after the first week. Median follow-up among ongoing survivors with a 
functioning graft was 45 months. Their 3-year actuarial patient and graft survival rates 
were 95% and 85% in African Americans, 89% and 78% in Hispanics, and 96% and 96% 
in non-African Americans, non-Hispanics, respectively (not significant). A potential 
shortcoming of this study was that bioavailability of tacrolimus was significantly lower 
among African Americans in comparison with the other patient subgroups (P=.002). 
While the incidence of biopsy-proven acute rejection was 20% (4/20) in African 
Americans, 19% (6/32) in Hispanics, and 13% (3/23) in non-African American, non-
Hispanic (not significant), chronic allograft dysfunction occurred more frequently among 
African Americans (10/20) in comparison with Hispanics (8/32) and non-African 
American, non-Hispanics (8/23) (P=0.08, log-rank test). In addition, there was a trend at 
6 and 12 months posttransplant for the mean serum creatinine to be less favorable among 
African American patients (P=0.08 and 0.07). No group had increased infection or 
malignancy. 
The most convincing study demonstrating the value of Campath® as an antibody 
induction therapy allowing early glucocorticoid withdrawal in renal-transplant recipients 
was a randomized, prospective trial recently published by Hanaway et al.18  In this study, 
the authors from five major US transplant programs compared induction therapy 
involving Campath® with the two most commonly used induction regimens in the US: 
Simulect® and Thymoglobulin®. They stratified patients into those at high immunologic 
risk (with a high risk defined by a repeat transplant, a peak or current value of panel-
reactive antibodies of 20% or more, or black race) or low immunologic risk. The 139 
high-risk patients received Campath® (one dose of 30 mg, in 70 patients) or 
Thymoglobulin® (a total of 6 mg per kilogram of body weight given over 4 days, in 69 
patients). The 335 low-risk patients received Campath® (one dose of 30 mg, in 164 
patients) or Simulect® (a total of 40 mg over 4 days, in 171 patients). All patients 
received Prograf® and Cellcept® and underwent a 5-day glucocorticoid taper in a 
regimen of early steroid withdrawal. The rate of biopsy-confirmed acute rejection was 
significantly lower in the Campath® group than in the conventional-therapy group at 
both 6 months (3% vs. 5%, P<0.001) and 12 months (5% vs. 17%, P<0.001). At 3 years, 
the rate of biopsy confirmed acute rejection in low-risk patients was lower with 
Campath® than with Simulect® (10% vs. 22%, P = 0.003), but among high-risk patients, 
no significant difference was seen between Campath® and Thymoglobulin® (18% vs. 
15%, P = 0.63). Adverse event rates were similar among all four treatment groups. Thus, 
these investigators provided strong evidence that Campath® induction therapy could be 
used for all renal transplant recipients, regardless of immunologic risk. Patients can 
expect equivalent or improved results and transplant centers can reduce the cost of 
immunosuppressive drugs. 
Based on these studies, and Dr. Rees’ experience with Campath® at the 
University of Cambridge during his transplant fellowship with Peter Friend and Professor 
Sir Roy Calne from 1996-1999, the University of Toledo Transplant program’s 
immunosuppressive regimen has utilized Campath® since March of 2006. Over the past 
nine years, we have evaluated three successive strategies. Beginning in March of 2006, 
we changed our standard of care immunosuppressive regimen from a conventional three-
drug approach utilizing Neoral®, Cellcept® and Prednisone to an approach based on the 
Pittsburgh experience. We started with Campath® and pre-operative steroid induction, 


 
                                   M. Rees        February 05, 2018 
7
followed by steroid-free maintenance on Prograf® monotherapy. After completing our 
first 50 patients with this regimen, we suspected an unacceptably high rejection rate and 
thus changed our approach to mirror the Northwestern experience by adding myfortic® 
to the maintenance immunosuppressive regimen. After accumulating an additional 100 
patients with this new regimen, we then assessed the relative efficacy of these two 
approaches. 
The following data is in preparation for publication. Data was collected 
retrospectively for all patients transplanted between 3/14/2006 to 12/31/2007 at The 
University of Toledo Medical Center. There were no exclusion criteria other than 
limiting data to two transplant surgeons resulting in a study population of 143 patients. 
The first study group was given Prograf® (P) alone (47 patients) following 
transplantation, with the later group receiving Prograf® and myfortic® (P/M) (96 
patients). Prograf® target level was 8 -12 ng/ml for both groups and myfortic® target 
dose was 720 mg PO bid adjusted for diarrhea and leukopenia.  All patients were treated 
with Valcyte® and Bactrim® prophylaxis for 6-12 months.  Review of the study 
populations showed no significance differences between the two immunosuppression 
groups for demographic details, death censored graft survival, patient survival, graft 
survival, rejection rate, one or two year creatinine level, severity of rejection (Banff 
score) or humoral rejection. Death censored graft survival rates after one year were 
97.8% (P) and 89.4% (P/M). Two year death censored graft survival was 88.9% (P) and 
85.6% (P/M).   One year patient survival was 93.6% (P) vs 95.8% (P/M) and two year 
patient survival was 93.6% (P) vs 90.6% (P/M). Creatinine level at one year was 1.7+1.2 
mg/dL (P) and 1.5+0.6 mg/dL (P/M) and at two years was 1.7+1.3 mg/dL (P) and 1.5+0.4 
mg/dL (P/M).  One year overall biopsy-proven rejection rates were 21.3% (P) vs 15.6% 
(P/M) and two year overall biopsy-proven rejection rates were 25.5% (P) vs 19.8% 
(P/M).  Though not achieving statistical significance, our analysis demonstrated a trend 
toward differences in response to therapy based on ethnicity. At two years, rejection rates 
were 22.6% for Caucasians in both study groups, whereas in African-Americans, 
rejection rates were 45.5% (P) and 13% (P/M) (p=0.0789). While observing a 45% 
rejection rate in African-Americans treated with Prograf® in the absence of myfortic®, 
this increased rejection rate did not correspond to worsening two year graft survival that 
was 90.9%.  Like the Miami experience, our data suggests caution with Campath® 
induction in African Americans, with two caveats: 1) our increased rejection rates were 
only seen in the absence of myfortic®; and 2) in the Miami study their results were 
limited by lower Prograf® bioavailability in African Americans. 
After publication of the study by Hanaway et al. in NEJM in late 2011, we 
decided that our 15-20% rejection rate with Prograf® and myfortic® with no steroid 
taper was unacceptable.18 Therefore, we modified our protocol to eliminate the second 
dose of 500 mg methylprednisolone intraoperatively and instead have spread this out by 
adding a steroid taper for the first five days post-operatively as was done in the Hanaway 
study. Since adopting this policy, we have seen a significant reduction in our rejection 
rate. 
 
Everolimus (Zortress®) inhibits the proliferation (growth or production) of T and B cells. 
It is an inhibitor of intracellular signal transduction (the relaying of signals inside a cell 
that communicates to the cell that it should activate or change) that targets the 


 
                                   M. Rees        February 05, 2018 
8
mammalian target of rapamycin (mTOR). The mechanism of action of everolimus 
appears to be distinct from those of calcineurin inhibitors. It forms a complex with the 
cytoplasmic protein FKBP-12 (intracellular tacrolimus-binding protein) and binds to and 
interferes with the function of FRAP. FRAP is a key regulatory protein which governs 
cell metabolism, growth and proliferation. The blockage of this signal leads to inhibition 
of cell cycle progression from G1 to the S phase (cell cycle growth phases); thus not 
allowing cells to develop and multiply. Combining everolimus and a calcineurin inhibitor 
gives rise to synergistic immunosuppressive properties.  
 
Tacrolimus (Prograf® or Hecoria®) inhibits T-lymphocyte activation, although the exact 
mechanism of action is not known. Experimental evidence suggests that tacrolimus binds 
to an intracellular protein, FKBP-12.  A complex of tacrolimus-FKBP-12, calcium, 
calmodulin, and calcineurin is then formed and the phosphatase activity (enzyme that 
frees or removes phosphate from a chemical reaction) of calcineurin is inhibited. This 
effect may prevent the dephosphorylation (removal of a phosphate group) and 
translocation (chromosome rearrangement) of nuclear factor of activated T-cells (NF-
AT), a nuclear component thought to initiate gene transcription for the formation of 
lymphokines (substances released by activated T-cells such as interleukin-2 or gamma 
interferon). The net result is the inhibition of T-lymphocyte activation (i.e., 
immunosuppression). 
 
Study Purpose and Rationale 
 
 
It is now clear that immunosuppressive strategies for renal transplantation achieve 
excellent short-term and medium-term results.  Unfortunately, the long-term results have 
not substantially improved in the last 20 years.  The reasons for this failure to achieve 
better long-term results are complicated and include such things as allowing older and 
sicker people to be recipients, using poorer quality donor kidneys and the complications 
associated with long-term immunosuppression.  Among the worst of the long-term effects 
of chronic immunosuppression are the nephrotoxicity of the calcineurin inhibitors and the 
myriad complications of steroids.  The goal of many now in the transplant field is to limit 
the exposure of transplant recipients to both steroids and calcineurin inhibitors.  The 
following protocol evaluates the reduction of calcineurin inhibitors in a protocol that has 
already successfully eliminated the long-term use of steroids.  Given the substantial 
experience with Campath® detailed above, the following study protocol will be offered 
to all patients undergoing renal transplantation at the University of Toledo University 
Medical Center. This is a small pilot study; multiple comparisons will be made for 
descriptive purposes only. 
 
Hypothesis: 
 
Our hypothesis is that conversion to everolimus (Zortress®), allowing the 
reduction of calcineurin inhibitors, will reduce nephrotoxicity (measured by increased 
creatinine clearance) and lengthen overall graft survival (measured by 2-year graft 
survival). 
 


 
                                   M. Rees        February 05, 2018 
9
Objectives: 
 
1. The primary objective of the study is to compare the efficacy and the effects on renal 
function of calcineurin-inhibitor reduction with conversion at 2 months after 
transplantation to Reduced Dose tacrolimus/everolimus in adult renal transplant 
recipients. Efficacy will be defined using two co-primary endpoints. 
a. A composite efficacy end point [treated biopsy-proven rejection 
(BPAR), graft loss, death or loss to follow-up]. 
b. Renal function at 24 months post transplantation using GFR as 
measured by the Modified Diet Renal Disease (MDRD) estimation. 
 
2. Secondary objectives will be to: 
a. Compare the safety and tolerability of the experimental arm compared 
to the historical control arm. 
b. Compare the presence of proteinuria as defined by spot urine protein to 
creatinine ratio greater than 1.0 in the experimental arm to the historical control 
arm. 
c. Compare the presence of hyperlipidemia in the experimental arm to the 
historical control arm. 
d. Compare the incidence of impaired glucose tolerance (IGT) as assessed 
by fasting blood sugar, HbA1c and need for hypoglycemic medications in the 
experimental arm to the historical control arm. 
e. Compare the incidence of mouth ulcers in the experimental arm to the 
historical control arm. 
f. Compare the incidence of GI complaints including diarrhea in the 
experimental arm to the historical control arm. 
g. Compare the incidence of leukopenia as defined by WBC less than 1.0, 
absolute neutrophil count less than 500 or the need for exogenous granulocyte 
stimulating factor administration in the experimental arm to the historical control 
arm. 
h. Compare the incidence of thrombocytopenia at one year as defined by 
platelet count less than 50 or need to discontinue one of the study medications for 
more than 30 days in the experimental arm to the historical control arm. 
i. Compare the incidence of neurotoxicity as defined by incidence of new 
onset seizure activity or tremors in the experimental arm to the historical control 
arm. 
j. Compare the incidence of pneumonitis in the experimental arm to the 
historical control arm. 
k. Compare the incidence of serious infections as defined by need for 
hospitalization in the experimental arm to the historical control arm. 
l. Compare the incidence of CMV infection as defined by need for 
hospitalization in the experimental arm to the historical control arm. 
m. Compare the incidence of BK infection as defined by blood titers 
requiring reduction in immunosuppressive dose in the experimental arm to the 
historical control arm. 


 
                                   M. Rees        February 05, 2018 
10 
n. Compare the incidence of BK nephropathy as defined by biopsy in the 
experimental arm to the historical control arm. Note that biopsies will not be 
required as part of the study but will only be done as part of the patient’s standard 
of care if rejection is suspected (i.e. if the serum creatinine increases by 25% and 
is not associated with elevated tacrolimus levels or clinical signs of 
dehydration/illness to account for elevated creatinine). 
o. Compare the incidence of malignancies including PTLD in the 
experimental arm to the historical control arm. 
p. Compare the incidence of cardiovascular complications such as 
dysrhythmias, coronary artery disease requiring intervention or myocardial 
infarction in the experimental arm to the historical control arm. 
q. Compare the incidence of the development of donor specific antibody 
(DSA) in the first 24 months post-transplant in the experimental arm to the 
historical control arm. 
 
Population: 
 
Patients will include all patients age 18 or over who are receiving renal 
transplantation regardless of prior transplant, ECD kidney, living donor kidney, level 
of sensitization, or BMI. 
 
Inclusion Criteria: At Screening: (2 months to 6 months after transplantation ± 10 days) 
 
• Male or female renal allograft recipients at least 18 years old. 
• Patients who have given written informed consent to participate in the study. If consent 
cannot be expressed in writing, it must be formally documented and witnessed, ideally 
via an independent trusted witness. 
• Patient who has received a kidney transplant from a deceased or living unrelated-
/related donor. 
• Recipient of a kidney allograft with a cold ischemia time (CIT) < 36 hours. 
• Female patients must have a negative pregnancy test prior to study enrollment. 
• Patients on CNI (tacrolimus and myfortic®) without steroid maintenance following 
Campath® induction. 
• Patients with an acceptable allograft function defined by a serum creatinine < 2.5 
mg/dL (250 μmol/L) and an actual eGFR (MDRD4) ≥ 30 mL/min/1.73m2 (without 
renal replacement therapy). 
• No evidence of rejection since the time of transplantation. 
 
Exclusion criteria At Screening: (2 months to 6 months after transplantation ± 10 days) 
 
• Recipient of ABO incompatible allograft or a positive cross-match. 
• Patient who is human immunodeficiency virus (HIV) positive. 
• Patient who received an allograft from a Hepatitis B surface Antigen (HBsAg) or a 
Hepatitis C Virus (HCV) positive donor. 


 
                                   M. Rees        February 05, 2018 
11 
• HBsAg and/or a HCV positive patient with evidence of elevated LFTs (ALT/AST 
levels ≥ 2.5 times ULN). Viral serology results obtained within 6 months prior to 
screening are acceptable. 
• Patient with severe restrictive (TLC < 50%) or obstructive pulmonary (FEV1 < 50) 
disorders. 
• Patient with severe allergy requiring acute (within 4 weeks of baseline) or chronic 
treatment that would prevent patient from potential exposure to everolimus, or with 
hypersensitivity to drugs similar to everolimus (e.g. macrolides). 
• Patients with a known hypersensitivity/contraindication to any of the 
immunosuppressants or their classes, or to any of the excipients. 
• Patient with severe hypercholesterolemia (> 300 mg/dL) or hypertriglyceridemia (> 400 
mg/dL) that cannot be controlled despite lipid lowering therapy. 
• Patient with white blood cell (WBC) count ≤ 1,000 /mm3 (and absolute neutrophil count 
of <500) or a platelet count ≤ 50,000 /mm3. 
• History of malignancy of any organ system, treated or untreated, within the past 5 years, 
regardless of whether there is evidence of local recurrence or metastases. (Localized 
basal cell carcinoma of the skin at any time, or small (less than 4 cm) or low-grade renal 
cancers, bladder cancers or treated prostate cancer with no evidence of disease after 2 
years are allowable) 
• Graft loss. 
• Patient on renal replacement therapy. 
• Patient who experienced biopsy proven rejection. 
• Proteinuria > 1 g/day (as calculated from the urinary protein-to-creatinine ratio). 
Protein-to creatinine ratios are only calculated if protein is 1+ or greater on urine dipstick 
as negative or trace amounts do not correlate to measurements near 1 g/day. 
• Patients with recurrence of Focal Segmental Glomerulosclerosis (FSGS). 
• Patient who has a current severe systemic infection according to the investigator 
judgment requiring continued therapy that would interfere with the objectives of the 
study. 
• Patients with ongoing wound healing problems, clinically significant infection 
requiring continued therapy or other severe surgical complication in the opinion of the 
investigator. 
• Presence of intractable immunosuppressant complications or side effects. 
• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
serum human chorionic gonadotrophin laboratory test (>5 mIU/mL) 
• Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, including women whose career, lifestyle, or sexual orientation 
precludes intercourse with a male partner and women whose partners have been sterilized 
by vasectomy or other means, UNLESS they are using two birth control methods. The 
two methods can be a double barrier method or a barrier method plus a hormonal method. 
o Adequate barrier methods of contraception include: diaphragm, condom (by the 
partner), intrauterine device (copper or hormonal), sponge or spermicide. 
Hormonal contraceptives include any marketed contraceptive agent that includes 
an estrogen and/or a progestational agent. Acceptable contraception methods will 
be discussed with all women of child-bearing potential. 


 
                                   M. Rees        February 05, 2018 
12 
o Reliable contraception should be maintained throughout the study and for 8 
weeks after study drug discontinuation. For women who become pregnant while 
using Myfortic® or within 8 weeks of discontinuing therapy, we will report the 
pregnancy to the Mycophenolate Pregnancy Reference Registry (1-800-617-
8191) and will strongly encourage the patient to enroll in the pregnancy registry. 
o Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate 
clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six 
months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and 
estradiol < 20 pg/mL] or have had surgical bilateral oophorectomy (with or 
without hysterectomy) at least six weeks ago. In the case of oophorectomy alone, 
only when the reproductive status of the woman has been confirmed by follow up 
hormone level assessment is she considered not of child bearing potential. 
 
Study Duration: 
 
We plan to enroll 11 patients per year.  Given this assumption, the enrollment will take 
five years. Adding two years of follow-up care, we will be able to complete the study in 7 
years. 
 
Study Design:   
 
1. Single center pilot study utilizing historical control 
2. A single treatment arm 
3. Eleven patients per year 
4. Five years to enroll 55 patients. 
5. Enroll all patients who meet the inclusion criteria at 2 months and up to 6 months 
(±10 days) post kidney transplantation and are willing to consent for this trial.   
6. Patients would have study visits, serum creatinine measurements and other 
clinically relevant parameters measured monthly until 6 months, then q3 months 
until 2 years post-transplantation. 
7. Graft survival would be measured by the absence of the need for dialysis. 
8. It would not be mandatory, but a renal biopsy would be recommended at 2 years 
to look for underlying early signs of calcineurin toxicity/chronic allograft 
nephropathy. 
9. Secondary endpoints would include such parameters as post-transplant diabetes, 
proteinuria, lipid levels, mouth sores, neurotoxicity, pneumonitis, CMV, PTLD, 
BK-nephropathy, malignancies, cardiovascular complications, etc. 
10. Our historical control will be composed of patients transplanted at the University of 
Toledo Medical Center between October 2011 and the beginning of this trial.  All of 
those patients will have been treated with the exact same protocol as in this study 
except that they will not have been converted to the treatment arm above, but will 
have remained on tacrolimus and myfortic®, unless the clinical situation warranted 
changing immunosuppression. We expect that the control group will consist of 
approximately 50-55 patients and will have similar demographics to the patients that 
will be enrolled in this trial, given that we will use the same inclusion and exclusion 
criteria to select all patients from October 2011 until the start of this trial to populate 


 
                                   M. Rees        February 05, 2018 
13 
the historical control group. The reason for October 2011 as the starting point for the 
historical control is that this is the date when we modified our protocol to add a five 
day taper of steroids immediately after transplantation. Prior to that we only gave 
steroids immediately prior to the transplantation procedure. Thus, to be consistent 
with the patients in this trial, we believe the most accurate historical control should 
have the same treatment with steroids perioperatively. We will utilize all patients 
available in the historical control dataset and will not attempt to match for the 
demographics present in the experimental arm. The control group will consist of a 
historical control; prospective patients who are not willing to participate in the study 
will not be considered part of the control group. 
11. For patients who are unable to tolerate the protocol-specified study treatment scheme 
or experience an adverse event, dose adjustments and/or interruptions of the 
medications in the treatment arm are permitted in order to keep the patient on the 
treatment. For everolimus (Zortress®), doses can be reduced by half or interrupted 
completely until an adverse event is resolved. If everolimus (Zortress®) is 
discontinued for longer than 14 consecutive days the patient must be discontinued 
from study treatment permanently. Maintaining the patients at a lower dose for 
tolerability issues is allowed. If tacrolimus (Prograf® or Hecoria®) is interrupted for 
longer than 14 consecutive days, study treatment must be discontinued permanently 
and the patient switched over to another of the center’s standard of care regimens.  
The criteria for removing a subject from the study medication to the standard of care 
immunosuppression may include any of the following circumstances: 
 
1. Discontinuation of study medication for longer than the study protocol allows (as 
described above) 
2. Pregnancy 
3. Voluntary withdrawal (withdrawal of consent to study) 
4. Lost to follow-up or failure to return for study visits 
5. Lack of compliance  
 
Patients may voluntarily discontinue from the study for any reason at any time or 
may be considered discontinued if they state an intention to withdraw, die or fail to 
return for visits, or become lost to follow-up for any other reason. Patients who elect 
not to remain on study medications will receive the UTMC standard of care 
immunosuppressive regimen at the discretion of the investigator.   
 
Brief Immunosuppressive Management: 
 
1. Induction therapy will consist of: 540 mg of myfortic® by mouth, 500 mg of 
Solu-medrol® IV, and 30 mg of Campath® IV pre-operatively.  . 
2. Post-operatively patients will be treated with tacrolimus to maintain a level of 10-
12 ng/ml for the first 2 months.  In the historical control arm, all of the patients 
will have been treated after the first three months such that the tacrolimus target 
level was reduced to 8-10 ng/ml until the end of the first year.  After the first year 
the tacrolimus target level would be 6-8 ng/ml in the historical control 
tacrolimus/myfortic® arm.  Concomitantly the historical control arm patients 
would have been treated post-operatively with 540 mg PO BID of myfortic® 


 
                                   M. Rees        February 05, 2018 
14 
unless diarrhea or leukopenia required lowering this dose. All patients would have 
received a five day taper of steroids at which time steroids were discontinued. 
3. In this proposed pilot study, after two months of maintenance therapy of 
tacrolimus and myfortic® as described above, all patients will receive the 
following treatment:  Their myfortic® will be weaned off quickly and everolimus 
initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once 
achieving a therapeutic dose of everolimus, the tacrolimus dose will be reduced to 
target a level of 3-5 ng/ml. 
 
Detailed Renal Transplantation Immunosuppression and Management Protocol 
 
1. 
The standard of care immunosuppressive regimen will be provided to all 
patients at the University of Toledo Medical Center for the first two months 
following renal transplantation. Beginning at 2 months (Screening) and not 
longer than 6 months (± 10 days) after renal transplantation, patients will be 
offered the opportunity to participate in a clinical trial to evaluate the efficacy 
and safety of calcineurin-inhibitor reduction. Informed consent will be 
obtained from all patients prior to enrollment. In addition, either at the time of 
evaluation for listing or actual listing on the deceased donor transplantation 
waiting list, patients will be counseled about immunosuppression trials being 
offered to patients undergoing renal transplantation at The University of 
Toledo Medical Center. 
2. 
The initial standard of care immunosuppressive regimen for patients 
undergoing renal transplantation at The University of Toledo Medical Center 
consists of Campath® induction, myfortic® and methylprednisolone (Solu-
medrol®) on call to the OR, with a five day steroid taper to no steroids by 
post-operative day five. Post-operatively patients will be maintained on 
tacrolimus (target level of 10 ng/ml) and myfortic® aiming for a dose of 540 
mg PO BID with adjustment for diarrhea and leukopenia. 
3. 
Patients are called to be admitted by the transplant coordinator after 
discussion with either the surgeon or nephrologists on call. Counseling about 
standard of care and investigational immunosuppressive regimens will be 
provided prior to proceeding with renal transplantation. 
4. 
A urology resident admits the patient to the hospital and makes sure that 
cardiac and other pre-transplant evaluation information is up to date.  The 
resident ensures that the patient does not have a history of recent infection, 
newly diagnosed cancers, recent cardiac events or newly diagnosed vascular 
complications. 
5. 
The transplant surgeon evaluates the recipient and consents them to use 
Campath® in an off-label fashion as the immunosuppressive induction agent 
either as part of the study described herein or as part of the standard of care. 
6. 
The patient is pre-medicated with: 
a. Tylenol® 650 mg PO 
b. Benadryl® 25 mg IV 
c. Pepcid® 20 mg IV 
d. Methylprednisolone 500 mg IV 


 
                                   M. Rees        February 05, 2018 
15 
e. myfortic® 540 mg PO 
7. 
Following the pre-medication above, the patient is administered Campath® 
over 2-3 hours.  The dose is 0.5 mg/kg for patients up to the weight of 60 kg.  
Any patient whose weight is > 60 kg is given a total dose of 30 mg Campath® 
intravenously.  Only one dose of Campath® is given on Day 0. 
8. 
Patients are to be observed closely for the possibility of a cytokine release 
response, although this response is much less frequent with Campath® than 
has been observed with OKT3®. 
9. 
The renal transplantation operation is then performed with the goal of 
completing the Campath® infusion prior to removing the arterial vascular 
clamps and re-establishing blood flow to the transplanted kidney.   
10. 
Just prior to removing the arterial vascular clamps, 40 mg of Lasix® and 12.5 
grams of mannitol will be administered IV. 
11. 
Post-operatively, during hospitalization (expected to last 4-5 days), the 
following medications are initiated: 
a. Tacrolimus 0.15 mg/kg PO BID adjusted to achieve a target (serum level 
of 10 ng/ml). 
b. myfortic® 540 mg PO BID is initiated and adjusted for diarrhea or 
leukopenia defined as a WBC < 1.0 or an absolute neutrophil count < 500. 
c. Valcyte® 450 PO mg daily for CMV-mismatched recipients or 450 mg 
PO every other day for non-CMV-mismatched recipients. 
d. Bactrim® DS one tab PO daily for PCP prophylaxis. 
e. Mycelex® Troche one troche PO QID. 
f. Flagyl® 500 mg PO TID to prevent Clostridium difficile infection. 
g. The following steroid taper will be followed: 
i. Post-op day 1: Prednisone 250 mg PO daily. 
ii. Post-op day 2: Prednisone 125 mg PO daily. 
iii. Post-op day 3: Prednisone 60 mg PO daily. 
iv. Post-op day 4: Prednisone 30 mg PO daily. 
v. Post-op day 5: Prednisone 15 mg PO daily. 
12. 
If delayed graft function is suspected, tacrolimus may be held for the first few 
days until the creatinine level begins to fall spontaneously. 
13. 
Target tacrolimus levels for the first 2 months post-operatively will be 10-12 
ng/ml with a target level goal of 10 ng/ml. After three months, the standard of 
care approach calls for the tacrolimus target level to be reduced to 8-10 ng/ml 
(with a target level of 8 ng/ml) until the end of the first year.  After the first 
year, patients without evidence of rejection would have their tacrolimus dose 
reduced to achieve a trough level of 6-8 ng/ml (with a target level of 6 ng/ml). 
This approach was used for patients in the historical control arm. 
14. 
No patients are to be treated for rejection without first obtaining a renal biopsy 
to confirm a cellular or humoral rejection. 
15. 
Cellular rejections scored as Banff 1 will be treated with three, daily pulses of 
250-500 mg methylprednisolone on three consecutive days and by confirming 
a therapeutic level of tacrolimus.  Cellular rejections scored as Banff 2 or for 
those rejections that are not responsive to steroids alone, Thymoglobulin® 
will be used for a 10-14 day course. Depending on the level of rejection, 


 
                                   M. Rees        February 05, 2018 
16 
ongoing steroid therapy can be administered after agreement by the treating 
physicians.  Generally, hospitalization is required for at least the first few days 
of the treatment of rejection using Thymoglobulin®.  During the first dose of 
Thymoglobulin®, blood pressure and vital signs will be monitored every 15 
minutes for the first hour, then every 30 minutes for the next two hours, then 
every one hour for the next 3 hours and then per routine protocol if stable. 
16. 
Humoral rejections will be treated with IVIG 100 mg/kg followed by a one 
volume exchange plasmapheresis on an every other day basis until the 
creatinine begins to fall or a decision is made to hold off on further treatment.  
In extreme cases, re-dosing Campath® can be considered or use of the anti-B 
cell agent, Rituximab (anti-CD20) can be used.  These decisions will be made 
after consultation between the transplant surgeon and attending nephrologists. 
17. 
The intention-to-treat concept will be applied to patients who experience 
biopsy-proven rejection to avoid missing outcomes. For patients in the study, 
low-dose myfortic® may be added back to the patient’s immunosuppression 
regimen. Short-term treatment with oral corticosteroids may be required, but 
long-term steroid use will be avoided. 
18. 
For patients with elevated, post-transplant creatinine but without biopsy 
proven evidence of cellular or humoral rejection, causes of elevated creatinine 
other than rejection should be considered.  These include intercurrent illness, 
dehydration, BK-nephropathy and tacrolimus toxicity.  Dose reduction of 
tacrolimus can be attempted to assess for the possibility of calcineurin-
inhibitor nephrotoxicity.  If dose reduction of tacrolimus is not acceptable, 
then everolimus (first choice) or Neoral® (second choice) will be used as 
replacement therapy. 
19. 
Upon discharge from the hospital, all patients will be treated with the 
following prophylactic medications: 
a. Valcyte® 450 mg PO daily to prevent subsequent CMV infection (unless 
leukopenia or other side effects warrant further dose reduction or 
discontinuation).  Valcyte® will be administered for 6 months if there is 
no CMV mismatch and for 12 months if there is a CMV mismatch. 
b. Bactrim DS® one tablet PO Monday, Wednesday and Friday to prevent 
subsequent pneumocystis carinii pneumonia.  In hospital desensitization 
with Dr. Nelson can be performed if the patient has a known sulfa allergy 
or Dapsone replacement can be used.  Bactrim® will be administered for 
at least one year following transplantation.  Length of therapy after one 
year will be determined by physician and patient preference. 
c. Mycelex® Troche one lozenge PO QID to prevent oral thrush.  Mycelex 
troche® therapy will be continued for 6 months post-transplantation. 
d. Flagyl® 500 mg PO TID to prevent Clostridium difficile infection only 
during in-hospital stays of transplant patients. 
20. 
BK viral titers will be assessed at three month intervals for the first year post-
operatively. 
21. 
Post-transplant PRAs (to determine the presence or absence of donor specific 
antibodies – DSA) will be assessed at the patient’s screening visit, at three 
month intervals for the first year post-operatively and every 6 months in the 


 
                                   M. Rees        February 05, 2018 
17 
second year post-operatively.  PRAs may also be assessed at the discretion of 
the principal investigator or measured as part of the patient’s standard of 
care/routine treatment. 
22. 
For patients who are prescribed myfortic® as part of an intention-to-treat 
adverse event, MPA levels will be assessed on an as needed basis. 
23. 
Patients who have CMV-mismatched kidneys may be followed with CMV 
viral titers.  Patients suspected of rejection episodes due to elevated creatinine 
levels should also be assessed for the possibility of BK-nephropathy by 
following urine cytology, looking for viral inclusion bodies on electron 
microscopy of biopsy specimens and by following BK viral titers in urine and 
or blood. 
 
Conversion at 2-6 Months (±10 days) to the Study Protocol  
 
1. Only patients who have reached the two month (± 10 days) post-operative mark 
without prior evidence of rejection will be offered the opportunity to participate in 
the study.  
2. At the two month mark (± 10 days), patients will be counseled about participation 
in the study and informed consent obtained prior to participation. Our control 
group will consist of a historical control; prospective patients who are not willing 
to participate in the study will not be considered part of the control group. 
3. Study participants will be maintained on the following immunosuppression 
regimen: 
a. Their myfortic® will be weaned off quickly and everolimus initiated to 
achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once 
achieving a therapeutic dose of everolimus, the tacrolimus dose will be 
reduced to target a level of 3-5 ng/ml with a mean of 4 ng/ml. 
b. As noted above, patients in the historical control group will have remained 
on tacrolimus and myfortic® according to the target levels outlined in #13 
above. Briefly, the tacrolimus target level would be reduced to 8-10 ng/ml 
(with a target level of 8 ng/ml) until the end of the first year and after the 
first year the tacrolimus target level would be further reduced to 6-8 ng/ml 
(with a target level of 6 ng/ml) if no evidence of rejection had been 
encountered. 
 
AE Reporting 
 
Any suspected serious adverse event (SAE) will be reported to the Novartis drug 
safety and epidemiology team overseeing the study within 24 hours of investigator 
awareness that an SAE has occurred. An SAE report form will completed for any serious 
adverse event occurring after the subject has provided informed consent and until 4 
weeks after the subject has stopped study participation. A serious adverse event (SAE) 
report form will be faxed to the number provided by the Novartis clinical trials team.  
 
The form will contain the following information: 
Investigator contact details 


 
                                   M. Rees        February 05, 2018 
18 
Date of report 
Subject description/study number / initials 
Subject treatment arm 
Study commencement date for subject 
Subject information - date of birth, sex, ethnicity, height and weight 
Subject’s past medical history 
Subject’s current immunosuppressive regimen and dosages 
SAE description  
Narrative description of the SAE and details of drug and non-drug treatment 
Onset Date and either Ongoing or End Date 
Concomitant medications 
Seriousness criteria (see below) 
Outcome (Death, Recovered or Recovered with Sequelae) 
Relationship to immunosuppressive medication regimen (suspected, not suspected 
or unknown).  
Assessment of causality including alternative explanations and consideration of 
any co-suspect medications based on the data available at the time. 
Signature of investigator 
 
Clinically significant follow-up information and/or new data that has become available 
will be faxed to Novartis within 24 hours of the investigator becoming aware that it is 
available. It will be indicated whether the new information should be added to the 
previously reported information or should replace the previously reported information. 
The report type will be labeled as “initial” or “follow-up”. Any SAEs that occur which 
are not associated with a previous report will require a new SAE report form. 
 
Seriousness criteria (as per Novartis established definitions) 
 
1. Death: The subject died. 
 
2. Life-threatening: The reporter believes the subject was at immediate risk of 
Death from the event as it occurred, e.g. aplastic anemia, anaphylaxis with 
peripheral circulatory collapse, suicide attempt by taking an excessive amount of 
study treatment. It does not include an event that, had it occurred in a more 
severe form, might have caused death. 
 
3. Required or prolonged inpatient hospitalization: The subject had to be admitted 
to hospital as an in-patient or hospitalization of the subject had to be extended as 
a result of an AE.  
An SAE form will not be completed if the hospitalization: 
- was for routine treatment or monitoring of the studied indication, not 
associated with any deterioration in condition 
- involved treatment, which was elective or pre-planned, for a pre-existing 
condition that is unrelated to the indication under study and did not 
worsen 
- was for general care, not associated with any deterioration in condition 
- involved only treatment on an emergency, outpatient basis for an event 
not fulfilling any of the other definitions of serious and not resulting in 
hospital admission. 


 
                                   M. Rees        February 05, 2018 
19 
 
4. Resulted in persistent or significant disability/incapacity: The event results in a 
substantial disruption of a person’s ability to conduct normal life functions. The 
extent of the disability does not need to be permanent. 
 
5. Congenital anomaly / birth defect: Any anatomical malformation or organ 
malfunction occurring in the offspring of a trial patient or subject. 
 
6. Other significant medical events: Medical and scientific judgment should be 
exercised in deciding whether expedited reporting is appropriate in other 
situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the subject or 
may require intervention to prevent one of the other outcomes listed above. There 
may be other events judged to be medically serious or which are significant by 
specification in certain clinical trials. 
 
Suspected transmission of an infectious agent via a medicinal product should 
always be considered serious and assessed as medically significant in the absence 
of any other seriousness criteria. Cases of newly diagnosed cancer must be 
reported on a SAE form under ‘other significant medical events’ or 
hospitalization, death etc as appropriate. Cases of overdose which are life-
threatening or result in death, hospitalization, significant disability or are 
considered medically significant should be reported on a SAE form. Overdose 
without clinical manifestation or leading to non-serious adverse events should not 
be reported on a SAE form. 
 
Any AE, SAE or unanticipated problem occurring as a part of this trial that is considered 
related or possibly related to the patient’s study treatment (immunosuppressive regimen) 
will also be reported to the University of Toledo Biomedical IRB Department for Human 
Research Protections on their corresponding internal adverse event reporting form within 
7 days of the investigator becoming aware of the event as required by policy and in 
conformance with HHS and FDA regulations. Any pregnancies will be reported to 
Novartis within 24 hours of the investigator becoming aware of it. 
 
The University of Toledo Biomedical IRB will have the authority to terminate IRB 
approval of research that is associated with unexpected serious harm to subjects.  
 
Statistical Section: 
 
 
This will be a small, pilot study to test whether conversion to everolimus 
(Zortress®), allowing the reduction of calcineurin inhibitors, will reduce nephrotoxicity 
(measured by increased creatinine clearance) and lengthen overall graft survival 
(measured by 2-3 year graft survival). As it is not a large study (55 patients, 11 patients 
per year), it is not powered to achieve statistical significance. The statistical significance 
will also be impaired by the use of a historical control group. However, the data 
generated will be published irrespective of the results, thus making the data available for 
meta-analysis.  
 
This trial is designed as a parallel-group study. Analysis of data for this design is 
simple and interpretation of the result is straightforward. Given the limited number of 


 
                                   M. Rees        February 05, 2018 
20 
patients in the trial it may not be meaningful to apply analysis of (co)variance for the 
statistical evaluation of a continuous variables such as creatinine clearance, but we will 
attempt to use this method with the guidance of our statistician, Dr. Khuder.19,20 Likewise,  
the limited number of patients in the trial may prevent meaningful analysis of time-to-event 
variables such as graft survival. Nonetheless, we will work with Dr. Khuder to use methods 
appropriate for survival analysis including the Kaplan-Meier method and Cox’s proportional 
hazards regression to see if meaningful differences exist between our study groups and our 
historical control.21,22 If warranted, for safety analyses the AEs and SAEs could be 
summarized by treatment group but no statistical tests performed due to the population size 
as a pilot study. In addition, the PI and Co-PI will meet with other members of the clinical 
transplant team to review the results of this study on a quarterly basis to ensure that no 
significant adverse events warrant the discontinuation of the trial. Given the small number of 
patients in the trial, we will analyze the data after we have enrolled 10 patients. If the study 
immunosuppression regimen has a > 40% Banff 2a rejection rate or greater than 20% patient 
death rate, then that arm will be prematurely terminated. Serious adverse events will also be 
analyzed and may serve as grounds for study discontinuation. 


 
                                   M. Rees        February 05, 2018 
21 
Evaluation Schedule  
 
Everolimus IIRP Pilot Study Evaluation and Visit Schedule 
Treatment Period 
 
Months 
 
Screening  
(Visit 1) 
Baseline 
(Visit 2) 
1 
(3) 
2 
(4) 
3 
(5) 
4 
(6) 
5 
(7) 
6 
(8) 
9 
(9) 
12 
(10) 
15 
(11) 
18 
(12) 
21 
(13) 
24 
(14) 
VISIT TIME WINDOWS 
2-6 Mos ± 10 days 
±7 days   
±14 days 
±30 days 
INFORMED CONSENT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
BACKGROUND 
INFORMATION 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MEDICAL 
HISTORY 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
INCLUSION/EXCLUSION 
CRITERIA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
TRANSPLANT 
INFORMATION 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
VIRAL SEROLOGY 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
BK VIRAL TITERS 
 
 
X 
 
X 
 
 
X 
X 
X 
 
X 
 
X 
EBV VIRAL TITERS (if neg) 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
CMV VIRAL TITERS (if neg) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
DSA EVALUATION 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
PHYSICAL EXAM 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VITAL SIGNS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PREGNANCY TEST  
(if applicable) 
X 
 
X 
 
X 
 
 
X 
X 
X 
 
X 
 
X 
PRIOR & CONCOMITANT 
MEDICATIONS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SAFETY LABORATORY 
TESTS** 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SERUM CREATININE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
STUDY MEDICATION 
ADMINISTRATION  
(if applicable) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EVEROLIMUS LEVEL 
(if applicable) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TACROLIMUS LEVEL 
(if applicable) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MYFORTIC LEVEL 
(if applicable) 
X 
 
 
 
X 
 
 
X 
X 
X 
 
X 
 
X 
OTHER IMMUNOSUPP 
THERAPIES 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SUSPECTED ACUTE 
REJECTION RECORD 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HOSPITALIZATION 
RECORD 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DIALYSIS RECORD 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE & INFECTION LOG 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SERIOUS ADVERSE 
EVENTS 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GRAFT LOSS 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
END OF TREATMENT /END 
OF STUDY 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
** Safety Labs include: Chem 13; AST, ALT, CBC w/ Diff; Lipid Profile; Magnesium, Inorganic Phosphate 
 


 
                                   M. Rees        February 05, 2018 
22 
 
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