Improving Transplant Medication Safety Through A Pharmacist-Empowered, Patient-Centered, Mhealth-Based Intervention (TRANSAFE Rx Study)
Phase: NA
Conditions: Medication Compliance
Sponsor: Medical University of South Carolina

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IMPROVING TRANSPLANT MEDICATION SAFETY THROUGH A PHARMACIST-
EMPOWERED, PATIENT-CENTERED, MHEALTH-BASED INTERVENTION  
(TRANSAFE Rx Study) 
 
Principal Investigator: 
David J Taber, PharmD, MS, BCPS 
Associate Professor, Division of Transplant Surgery 
Medical University of South Carolina 
96 Jonathan Lucas Street; CSB 409 
Charleston, SC 29425 
 
 
Supported by: 
Agency for Healthcare Research and Quality  
(AHRQ) 

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TABLE OF CONTENTS 
 
A 
INTRODUCTION ...................................................................................................... 4 
A1 
STUDY ABSTRACT ............................................................................................... 4 
A2 
PRIMARY HYPOTHESIS ........................................................................................ 4 
A3 
PURPOSE OF THE STUDY PROTOCOL ................................................................... 4 
B 
BACKGROUND ....................................................................................................... 5 
B1 
PRIOR LITERATURE AND STUDIES ........................................................................ 5 
B2 
RATIONALE FOR THIS STUDY ............................................................................... 7 
C 
STUDY OBJECTIVES ............................................................................................. 8 
C1 
PRIMARY AIM ...................................................................................................... 8 
C2 
SECONDARY AIM ................................................................................................ 8 
D 
STUDY DESIGN ...................................................................................................... 8 
D1 
OVERVIEW OR DESIGN SUMMARY ........................................................................ 8 
D2 
SUBJECT SELECTION AND WITHDRAWAL .............................................................. 8 
2.a 
Inclusion Criteria ............................................................................................ 8 
2.b 
Exclusion Criteria ........................................................................................... 8 
2.c 
Ethical Considerations ................................................................................... 9 
2.d 
Subject Recruitment Plans and Consent Process .......................................... 9 
2.e 
Randomization Method and Blinding ........................................................... 10 
2.f 
Risks and Benefits ....................................................................................... 10 
2.g 
Early Withdrawal of Subjects ....................................................................... 12 
2.h 
When and How to Withdraw Subjects .......................................................... 12 
2.i 
Data Collection and Follow-up for Withdrawn Subjects ................................ 12 
D3 
STUDY INTERVENTION ....................................................................................... 13 
3.a 
Treatment Regimen ..................................................................................... 13 
3.b 
Method for Assigning Subjects to Treatment Groups ................................... 18 
3.c 
Subject Compliance Monitoring ................................................................... 18 
3.d 
Blinding of Study Drug ................................................................................. 18 
E 
STUDY PROCEDURES ......................................................................................... 19 
E1 
SCREENING FOR ELIGIBILITY .............................................................................. 19 
E2 
SCHEDULE OF MEASUREMENTS ......................................................................... 19 
E3 
SAFETY AND ADVERSE EVENTS ......................................................................... 20 
3.a 
Safety and Compliance Monitoring .............................................................. 20 
3.b 
Medical Monitoring ...................................................................................... 21 
i 
Investigator only .......................................................................................... 21 
ii 
Independent expert to monitor ..................................................................... 21 
iii 
Institutional Data and Safety Monitoring Board ............................................ 21 
iv 
Independent Data and Safety Monitoring Board .......................................... 21 
3.c 
Definitions of Adverse Events ...................................................................... 22 
3.d 
Classification of Events ................................................................................ 22 
3.e 
Data Collection Procedures for Adverse Events .......................................... 22 
E4 
STUDY OUTCOME MEASUREMENTS AND ASCERTAINMENT ................................... 22 

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F 
STATISTICAL PLAN ............................................................................................. 25 
F1 
SAMPLE SIZE DETERMINATION AND POWER ........................................................ 25 
F2 
INTERIM MONITORING AND EARLY STOPPING ...................................................... 25 
F3 
ANALYSIS PLAN ................................................................................................ 26 
F4 
STATISTICAL METHODS ..................................................................................... 27 
F5 
MISSING OUTCOME DATA ................................................................................ 226 
F6 
UNBLINDING PROCEDURES .............................................................................. 226 
G 
DATA HANDLING AND RECORD KEEPING ...................................................... 227 
G1 
CONFIDENTIALITY AND SECURITY ..................................................................... 227 
G2 
TRAINING ......................................................................................................... 28 
G3 
CASE REPORT FORMS AND SOURCE DOCUMENTS .............................................. 28 
H 
STUDY ADMINISTRATION ................................................................................. 227 
H1 ORGANIZATION AND PARTICIPATING CENTERS ..................................................... 227 
H2 FUNDING SOURCE AND CONFLICTS OF INTEREST ................................................. 228 
H3 COMMITTEES ..................................................................................................... 228 
H4 SUBJECT STIPENDS OR PAYMENTS ........................................................................ 29 
H5 STUDY TIMETABLE ................................................................................................ 29 
I 
PUBLICATION PLAN ............................................................................................ 29 
J 
ATTACHMENTS .................................................................................................... 30 
K 
REFERENCES....................................................................................................... 71 
 

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A Introduction 
A1 Study Abstract 
 
Although the contemporary use of immunosuppression regimens have dramatically 
reduced the incidence of acute rejection, long-term graft survival continues to be 
suboptimal in kidney transplantation.  Studies suggest that adverse drug events and 
medication errors, both of which encompass medication safety issues, may be a 
predominant cause of graft loss.  However, despite kidney transplant recipients being at 
high-risk for medication safety events, there is limited information surrounding the 
incidence, etiologies and outcomes of medication (med) errors and adverse drug events 
within this population.  Our preliminary research has demonstrated that significant 
medication errors, predominantly due to patient-related factors, occur in nearly two-thirds 
of kidney transplant recipients, leading to hospitalization in one out of every eight 
patients.   Recipients that develop clinically significant med errors are at considerably 
higher risk of deleterious clinical outcomes, most significantly graft loss; these patients 
also develop substantially more adverse drug events, readmissions and acute rejections. 
Researchers have also demonstrated feasibility and high acceptability of mobile health 
(mHealth) technology use to bridge communication gaps that often lead to med safety 
issues.  Smartphone and home-based monitoring technology has a very high 
penetration rate within this population.  These studies establish that a pharmacist-
empowered, patient-centered, mHealth-based intervention provides an innovative and 
highly promising opportunity to improve med safety in kidney transplantation.  It is within 
this context that the Improving Transplant Medication Safety through a Pharmacist-
Empowered, Patient-Centered, mHealth-Based Intervention (TRANSAFE Rx) study was 
developed.  The primary goal of the TRANSAFE Rx study is to demonstrate significant 
reductions in med safety issues leading to reduced healthcare resource utilization in 
kidney transplantation through a pharmacist-led, mHealth-enabled, intervention.  This 
study will provide detailed and novel information on the incidence, etiologies and 
outcomes of med errors and adverse drug events in this high-risk population; while also 
demonstrating the effectiveness of this intervention on reducing the incidence and 
impact of med safety issues in kidney transplantation.  The enduring goals of this study 
are to demonstrate a highly effective, efficient and deployable method to improve 
medication safety in high risk patient populations with the long-term objective of 
disseminating this promising technology and intervention across multiple patient types 
and healthcare environments. 
A2 
Primary Hypothesis 
 
Hypothesis 1: Patients in the intervention arm will have significantly fewer med errors 
and adverse drug events, as compared to the usual care arm, at the end of the 12-
month study 
 
Hypothesis 2: The intervention arm will have significantly fewer healthcare encounters 
(clinic visits, ED visits and hospitalizations), leading to reduced costs, as compared to 
the usual care arm, at the end of the 12-month study 
A3 
Purpose of the Study Protocol 
Due to the complexities and toxicities associated with their immunosuppressive 
medication regimens, kidney transplant recipients are at high-risk of developing 
medication safety issues which can lead to hospitalization, increased healthcare 
expenditures and ultimately, graft loss.  Founded on preliminary information, the use of 
pharmacists and mHealth technology provide a promising and innovative approach to 

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improve medication safety in high-risk patients.  The ultimate goal of this research is to 
demonstrate how patients, pharmacists and technology can work hand-in-hand to 
optimize medication-related outcomes and reduce healthcare expenditures. 
B 
Background 
B1 Prior Literature and Studies 
Within kidney transplantation, despite dramatic improvements in acute rejection rates, 
long-term graft survival has not improved to nearly the same degree.  Since 2003, there 
has been a 50% reduction in acute rejection rates; yet, during this same time period, the 
kidney allograft half-life has only increased by a modest 0.6 years.(3, 4)  The most 
recent report from the Scientific Registry of Transplant Recipients (SRTR) demonstrates 
a historically low one-year acute rejection rate of <10%, with a suboptimal five-year graft 
survival rate of 70%.(1)  Medication safety issues, which encompass both medication 
errors and adverse drug events, are a predominant cause of deleterious clinical 
outcomes in kidney transplant recipients; most notably, graft loss.  
 
We, and others, have demonstrated that approximately two-thirds of transplant 
recipients will experience at least one medication error. (8-10) Of more concern, nearly 
one in eight kidney transplant recipients will experience a medication error which directly 
contributes to hospitalization and more than doubles the risk of graft loss (Figure 1).  
These medication errors are usually the result of unintentional medication non-
adherence (MNA); patients have difficulty obtaining medications or forgetting to take 
medications in a timely fashion.(11) MNA, usually due to unintentional patient-level 
factors, has now been recognized as a major contributor to late acute antibody mediated 
rejection (AMR), the development of donor specific antibodies (DSA) and subsequent 
graft loss.  In a prospective multicenter observational study, 315 kidney transplant 
recipients were followed for roughly three years post-transplant; 47% of the 50 allografts 
that failed during follow-up were due to AMR.  Thirty-two percent of patients were 
identified as having MNA and approximately one-half of all AMRs were due to MNA.  
Remarkably, MNA was 10 times more frequent in patients with graft failure (32% vs. 3%, 
p<0.001).(23)  As most MNA is unintentional, with the proper monitoring tools and 
clinical follow-up, this devastating risk factor appears to be modifiable.  
 
 

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Although contemporary immunosuppression is extremely effective at preventing 
rejection, adverse drug events are nearly universal and associated with significant post-
transplant morbidity.  Several studies suggest that adverse drug events, particularly 
surrounding infection from over-immunosuppression and calcineurin inhibitor 
nephrotoxicity, may be a predominant cause for the discordance noted between 
reductions in acute rejection and lack of improvements in graft survival.  In 2006, 
Parasuraman, et al. showed that infectious etiologies surpassed rejections as the 
leading cause of death-censored graft lost.(6)  Our formative research demonstrates that 
immunosuppressant adverse drug events are correlated with medication errors; patients 
that experience medication errors leading to hospitalization have 2.3 times the risk of 
developing at least three adverse drug events (p=0.020, Table 1).(11)  In other chronic 
disease states, adverse drug events have clearly been established as a major risk factor 
for MNA.(24-27)  Therefore, early recognition of adverse drug events in kidney 
transplant recipients will likely help prevent downstream clinical sequelae, including MNA 
and irreversible immunosuppressant toxicities.  Research demonstrates that clinical 
pharmacists have the unique education and training to identify these events early, while 
also developing strategies to mitigate or resolve the associated sequelae.(13, 14, 28-32) 
 
 
 
The impact of kidney allograft loss on clinical and economic outcomes cannot be 
overstated.  Annual death rates are more than three times higher in those with kidney 
allograft failure (9.4%), compared to those with a functioning transplant (2.8%).(33)   A 
well-functioning kidney allograft has also been shown to dramatically reduce the 
progression of cardiovascular disease and associated events.(28-30)  In terms of cost, 
kidney transplantation is clearly cost-effective.  However, due to high and varied peri-
operative costs associated with this surgery, the break-even point can range from 2 to 
11 years after transplant.(31, 32)  Once a kidney allograft fails, patients return to dialysis 
and costs to provide care accrue at a significantly higher rate.(33, 34)  Our research 
indicates that kidney transplant recipients that experience clinically significant medication 
errors spend five more days in the hospital for readmissions, costing more than $18,000 
per case.(11)  These data establish the need for innovative interventions designed to 
improve medication safety in kidney transplant recipients by reducing medication errors 
and adverse drug events;(7) Such medication safety improvements are needed to 
demonstrate significant progression in the optimization of long-term graft outcomes and 
patient survival, while considerably reducing the costs to provide high value care in this 
high-risk group of patients.  Control of chronic health conditions, exacerbated by 
immunosuppressive therapies, also has a major impact on allograft and patient 
survival.(34,35) Due to the high prevalence of hypertension and diabetes in kidney 
transplant recipients and the interplay between these diseases and graft outcomes, this 

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is an ideal population to test mHealth systems and their effects on outcomes for future 
application in a more widespread population. 
B2 
Rationale for this Study 
Kidney transplantation is considered the preferred treatment option for patients with end-
stage renal disease, with more than 140,000 patients living in the U.S. with a functioning 
transplant. The use of potent contemporary immunosuppression has significantly 
decreased acute rejection rates, with current one year rates of <10%, compared to 30 to 
40% three decades prior.(1-3)  Despite this, long-term renal allograft survival remains 
largely unchanged during this time period.  Studies have demonstrated that predominant 
causes of graft loss are driven by immunosuppression adverse drug events (patient 
harm related to a med) and rejection from med non-adherence.(4-6)  These origins of 
graft loss encompass issues directly related to med safety.  Current immunosuppression 
regimens are highly effective but carry the burdens of considerable toxicities and 
exceeding complexity.(7)  These attributes place a transplant patient at high risk of 
developing adverse drug events and med errors.  Despite this, there are limited studies 
analyzing the incidence, etiologies and outcomes associated with med safety issues.(8, 
9)  Our formative research has demonstrated that med errors (taking a med in a manner 
not intended), predominantly due to patient-related factors, occur in nearly two-thirds of 
kidney transplant recipients, leading to hospitalization in one out of every eight 
recipients.(10,11) We have also found that recipients that develop clinically significant 
med errors are at considerably higher risk of deleterious clinical outcomes, most 
significantly graft loss; these patients also develop substantially more adverse drug 
events, readmissions and acute rejections.(10,11) 
 
Our team has published non-controlled quality improvement initiatives demonstrating 
reduced med errors, adverse drug events, hospital length of stay and readmissions 
through pharmacist-led interventions.(12-15)  These studies provide foundational 
evidence that structured interventions can improve outcomes associated with med safety 
issues in transplant, but further data are required both to better understand contributing 
risk and etiologies, while also testing effectiveness of novel interventions in a 
prospective, controlled manner. We have demonstrated feasibility and high acceptability 
of mobile health (mHealth) technology to bridge communication gaps that often lead to 
med safety issues. Our transplant recipients have doubled smartphone use to over 60% 
from 2012 to 2015.(16-18)  Almost 90% of survey respondents indicated they were 
comfortable with mHealth monitoring and felt it improve timely patient-provider 
communication.(17)  Transplant recipients were central to successful development of a 
mHealth medical regimen self-management program which the proposed program builds 
upon.(16,19)  These data establish that a pharmacist-empowered, patient-centered, 
mHealth-based intervention provides an innovative and promising opportunity to improve 
med safety in kidney transplantation. Our mHealth programs and that of others have 
been successful in improving physical markers for various chronic diseases, including 
those present in transplant recipients (e.g. BP for hypertension); however cost-
effectiveness of these efforts have yet to be adequately demonstrated. (16, 19-22)  
 
The central hypothesis for the TRANSAFE Rx study is that a mHealth technology-
enabled pharmacist intervention will significantly reduce med safety issues and lead to 
reduced healthcare resource utilization in kidney transplantation.   
This study will provide novel data on the incidence and outcomes of med safety issues in 
transplantation, while demonstrating the effectiveness of a pharmacist-led, patient-
centered, mHealth intervention.  The enduring goals of this study are to demonstrate a 

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highly effective, efficient and deployable method to improve med safety in a high-risk 
patient population and disseminate this mHealth enabled program across multiple 
patient types and healthcare environments. 
C 
Study Objectives 
C1 Primary Aim 
• 
Determine the incidence, severity and etiologies of med errors and adverse drug 
events in kidney transplant recipients and compare these between the 
intervention and control cohorts. 
C2 
Secondary Aims 
• 
Measure the total resources utilized (hospital, outpatient, staff effort) to provide 
care and compare these between the intervention and control cohorts. 
 
• 
Measure the impact of med errors and adverse drug events on clinical outcomes, 
including acute rejections, infections, graft loss and death (exploratory aim) 
 
D 
Study Design  
D1 
Overview or Design Summary 
TRANSAFE Rx is a 12-month, parallel two-arm, 1:1 randomized controlled clinical trial, 
involving 136 participants (68 in each arm) and measuring the clinical and economic 
effectiveness of a pharmacist-led intervention, which utilizes an innovative mHealth 
application to improve medication safety and health outcomes, as compared to usual 
post-transplant care. The planned study design and interventions of this project were 
developed from the aforementioned foundational studies.  These preliminary studies 
provided insight into interventions that were clinically effective, efficiently implementable, 
had a high-rate of patient acceptability and were capable of being scalable to a wide-
array of patient populations. It is within this framework that the investigators have 
designed the TRANSAFE Rx study. 
D2 
Subject Selection and Withdrawal  
2.a 
Inclusion Criteria  
1) Kidney transplant recipient between 6 and 36 months post-transplant 
2) At least 18 years of age 
3) Transplant MD agrees that patient is eligible to participate 
2.b 
Exclusion Criteria  
1) Multi-organ recipient 
2) Patient is incapable of: 
a. Measuring their own blood pressure  
b. Measuring their own glucose (if subject has diabetes) 
c. Self-administering medications 
d. Speaking, hearing and reading English 
e. Utilizing the mHealth application, after training 

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2.c 
Ethical Considerations  
 
Ethical considerations for randomized, controlled trials include informed consent, risk of 
harm by the intervention, and risk of loss of confidentiality. Subjects eligible for this study 
will undergo an informed consent process with a study coordinator that is trained in the 
process and has completed the Collaborative IRB Training Intiative (CITI) offered online 
by the University of Miami. The PI of the study will be available for any questions and the 
subject will be provided adequate time to make an informed decision, as described in 
section 2(c). Because the intervention is technological, the greatest additional risk to the 
subjects is loss of confidentiality. Only data that is necessary for the purpose of the study 
will be collected. Subject data will only be available on password-protected devices and 
only encrypted data will be transferred. 
 
Protection of Human Subjects:  MUSC researchers are allowed the privilege of 
working with human subjects under normal assurance to the government that such 
research complies with regulations protecting human subjects. The university has a 
federal-wide assurance for research with human subjects and is in compliance with 
federal policy governing use of human subjects. Investigators involved in human subject 
research at MUSC are required to complete the Collaborative IRB Training Initiative 
(CITI) offered on line by the University of Miami. In addition, all human subject protocols 
are reviewed through the MUSC Institutional Review Board (IRB). The Office of 
Research Integrity coordinates the activities of three IRB committees, involving faculty 
members as well as representatives in the legal, ethical, religious, civic, and business 
communities. 
 
Compliance:  The MUSC University Compliance Program is a proactive program to 
ensure full agreement with all applicable policies, procedures, laws and regulations. This 
involves a confidential Compliance Helpline to encourage all members of the MUSC 
community to ask questions or voice concerns about laws and regulations on such 
topics as coding and billing, research integrity, professional ethics, human subjects, 
animal research, biological safety, conflict of interests, and patient confidentiality. The 
program office proactively trains employees and facilitates discovery of concerns, 
followed by appropriate investigation into problem areas and timely resolution of issues. 
This program directly assists MUSC’s management at all levels in maintaining and 
enhancing an environment where ethics are paramount considerations in strategic and 
operational decisions throughout the organization. 
 
2.d 
Subject Recruitment Plans and Consent Process 
 
Subject Identification/Recruitment:  
Adult (≥18 years old at the time of transplant) solitary kidney transplant recipients 6 to 36 
months post-transplant that meet study eligibility will identified through review of patients 
visiting the kidney transplant clinic as part of usual care and approached by research 
personnel for consideration for participation. 
 
Informed Consent:  
Authorized research personnel will approach patients to explain the study and offer the 
opportunity to participate in the study. The personnel who will obtain consent will have 
completed Human Subjects Protection Training. This research study will be explained in 

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lay terms to each potential research participant. In compliance with the informed consent 
process outlined in CFR Title 21 Part 50, the authorized personnel will conduct a face-to-
face meeting with the study candidate to review all of the required elements of informed 
consent. The potential study participant will sign an informed consent form before 
undergoing any screening study procedures. The original consent form will be kept with 
the subject’s file in the office. A copy of the consent will be given to the patient and 
another copy will be put in his/her chart. At the time of consent, patients will be assured 
that their care will not be affected in any way if they choose not to participate in the 
study. Patients will also be reminded that it is their right to withdraw their participation in 
the study at any time.   
2.e 
Randomization Method and Blinding 
 
Randomization Method: 
Whether a patient is in the intervention group or the control will be by random selection 
using a random number generator in a simple blocked manner (blocks of 8). 
 
Blinding: 
This is an open-label study, so subjects and the research team will be aware of the study 
assignment. Due to the nature of the intervention, blinding of the subject and research 
staff is unable to be performed. In order to minimize bias, data for outcomes will be 
collected by a blinded study coordinator. 
2.f 
Risks and Benefits 
There are minimal risks to patient safety during the completion of this study within the 
intervention arm and no risks with regards to study interventions within the control arm. 
This study will not involve requiring patients to take any experimental medications.  All 
patients, regardless of randomization will receive standard usual care as part of this 
study.  Any adjustments or changes made to the patient’s medication regimen in the 
intervention group will be approved by a transplant physician.  There will be increased 
monitoring and scrutiny of patient’s home blood pressures, glucoses and medication 
regimens.  All documented medication errors and adverse drug events will be identified 
by a blinded research coordinator at the same frequency and methodology across 
intervention and control patients.  This will minimize the likelihood of identifying higher 
rates of medication safety issues in the intervention group. The risk associated with the 
intervention arm is in loss of patient confidentiality, which will be mitigated through the 
use of HIPPA compliant data encryption on mobile devices and storage of PHI on 
password protected databases behind the MUSC firewall. 
 
Although it is expected that this will improve medication safety, it may also increase 
stress on patients and increase the potential of identifying false positive information.  We 
will minimize the risk of this causing harm to study patients by ensuring all data is closely 
monitored by a highly trained clinical pharmacist.  All interventions made based on this 
will be reviewed and approved by a transplant physician. 
 
The study research coordinator will identify medications errors and adverse drug events 
within both arms, but clinicians will not be privy to this information as part of usual care.  
However, usual care and follow up will ensure all patients in both arms receive the most 
up to date and effective care that is provided in the current health care environment.  
Should these identified, but not acted upon, medication safety issues induce patient 

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harm, it will be closely tracked by the research personnel and reported as detailed in the 
DSMP.  Through this plan, we are minimizing all potential risks for patients participating 
in this study. 
 
Unknown Risks: The researchers will inform patients if they learn anything that may alter 
patient’s views about participating in the study.  Since all patients in both arms of this 
study are receiving standard of care, no additional risks are foreseen with this study. 
 
Adequacy of Protection Against Risks 
 
Recruitment and Informed Consent 
 
Participation in the study will be voluntary.  Patients who have received a renal 
transplant 6 to 36 months post-transplant will be identified during routine clinic visits for 
usual care.  Subjects who meet inclusion criteria for the study will be asked about their 
desire to participate.  Patients will be required to complete an informed consent 
document to ensure they understand the goals, risks, and potential benefits of the study 
before any research related activities occur. 
 
Protection against Risk 
 
There should not be any extensive risks to patient safety during the completion of this 
study:  no investigational medications will be used and all changes to patient’s current 
medication regimens will be made in accordance with and under the direct approval of a 
transplant physician.  In order to protect subjects against any risk regarding loss of 
personal information, all obligations under the Health Information Portability and 
Accountability Act (HIPAA) will be met.  Additionally, all data will be collected and stored 
through the secure network server and behind the MUSC firewall.  We will use electronic 
CRF forms approved by the IRB to gather all study information.  Data will only be stored 
on campus computers under the MUSC secure network.  Data collection forms will be 
maintained within an office, which is a locked office facility on campus.  Only approved 
study members will have access to patient data.   
 
Any data or information shared for dissemination will be de-identified and the 
confidentiality of all participants will be strictly maintained.  The only persons with access 
to protected health information (PHI) will include study investigators, research 
coordinators and those approved by the MUSC IRB.  All data will be secured on MUSC 
servers, behind firewalls, with passwords protecting entry in these systems.  All PHI will 
be obtained and managed in accordance with the HIPAA Privacy Rule (45 CFR Parts 
160 and 164). 
 
Increased scrutiny and remote monitoring using technology and a clinical pharmacist 
may lead to an increased awareness and documentation of medication side effects and 
adverse drug events.  However, we expect these to be identified and managed very 
early in their course, before they can induce harm to the patient requiring further health 
care interventions.  Early identification and resolution of medication errors, side effects 
and adverse drug events is the primary factor that we expect to be the mediator of 
reduced health care encounters and costs.  To ensure this is occurring in a safe manner, 
the DSMP will include detailed monitoring of health care encounters and clinical 
outcomes, including acute rejection episodes and graft function.  If there are signals that 
the intervention is actually inducing higher rates of these incidents, then the designated 

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safety officer, an experienced transplant physician, has the authority to stop enrollment 
and/or close the study (section E3.a).  We fully expect these event rates to reduce in the 
intervention arm, as compared to the control arm.  We do, however, have a 
comprehensive plan to address issues if this is, in fact, not the case. 
 
Potential Benefits of the Proposed Research to the Subjects and Others 
 
Patients in the intervention group may have reduced incidence and burdens associated 
with medication safety issues.  This may potentially lead to reduced health care 
associated encounters, visits to the clinic and/or hospital and costs.  Regardless, the 
completion of this study will produce data that will lead to a better understanding of the 
incidence, severity, root cause and potential outcomes associated with medication safety 
issues within kidney transplant recipients.  This information can be utilized to design and 
test different intervention strategies to reduce these events, should the proposed 
intervention within this study fail to demonstrate meaningful results. 
 
Importance of the Knowledge to be Gained 
 
It is hoped that the information gained from the study will help the researchers learn 
more about the incidence, severity, root cause and potential outcomes associated with 
medication safety issues within kidney transplant recipients and determine if a 
pharmacist-led mHealth enabled intervention can potential reduce these events. 
  
2.g 
Early Withdrawal of Subjects 
If a study subject desires to prematurely terminate the study intervention, if possible, a 
visit will be scheduled with the Principal-Investigator (PI) or designee within seven days 
to evaluate the reason for early termination.   It will be clarified whether they are 
terminating from all components of the trial or only from the primary intervention 
component of the trial.  Ultimately, subjects have the autonomy to withdraw from the 
study or stop the intervention if they so desire. 
2.h 
When and How to Withdraw Subjects  
Subjects will complete the study at the end of the 12-month follow up period or at the 
time they wish to prematurely terminate the study. 
2.i 
Data Collection and Follow-up for Withdrawn Subjects  
If a study subject wishes to terminate the study intervention, but are willing to continue to 
report outcomes, they will have outcome data collected until their final study visit. If any 
subject wishes to terminate from all aspects of the study and withdraw, data collection 
will cease from that point on and outcomes will be censored at that point for data 
analysis. 
 
 
D3 
Study Intervention  
3.a 
Treatment Regimen  
 

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Intervention Cohort 
 
Patients randomized to the intervention cohort will be provided the same usual care as 
the control cohort.  In addition, this cohort of participants will receive clinical pharmacist-
led supplemental medication therapy monitoring and management, utilizing a 
smartphone-enabled mHealth application, integrated with televisits and home-based 
monitoring of blood pressures and glucoses (when applicable).  Subjects in this cohort 
will be provided with a mobile device/data plan if they are not current owners of an 
iPhone.  All will also be provided with a Bluetooth-enabled, automated, cuff-style bicep 
home blood pressure monitor and a Bluetooth-enabled digital home blood glucose 
monitor.  On the mobile device, a HIPPA compliant app developed by our collaborative 
group will be installed that displays the patient’s medication list and alerts them when it 
is time to take each medication, requiring them to indicate if the medication was taken 
for adherence tracking. Through the app, medication regimen-specific symptom surveys 
will be pushed to patients that ask the frequency and severity of common side effects of 
their medications. The intervention will include a clinical transplant pharmacist 
telemonitoring patient medication adherence and blood pressure/glucose readings (if 
applicable) weekly and scheduling telehealth visits with patients, as outlined in Table 2.  
 
  
 
The clinical transplant pharmacist will be alerted by the patient if there are medication 
changes made by outside providers, by way of making adjustments to the medication 
regimen in the mobile app. At this point, the patient will be contacted to evaluate the 
medication change and determine if the adjustment to the regimen is safe and effective.  
If the pharmacist deems this change to be of concern, they will work with the patient and 
transplant physician to alter the regimen in an appropriate manner.  In addition, the 
pharmacist will be alerted if the patient has evidence of significant nonadherence (≥20% 
missed self-reported medication doses in the course of a week), if they have blood 
pressure or glucose values that fall into critical ranges or if there are alarming trends in 
their readings or symptom assessments from surveys.  Upon receiving these alerts, the 
pharmacist will communicate with the patient, determine the root cause and coordinate 
care with other care providers as delineated at the bottom of Figure 4.   
 

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During televisit encounters, the transplant pharmacist will conduct a thorough medication 
review, evaluate for signs and symptoms suggestive of medication safety issues, screen 
for drug-drug and drug-disease interactions and provide recommendations to resolve 
identified issues to the patient and/or provider, when applicable.  The clinical pharmacist 
will be alerted and evaluate each patient when making a transition of care (inpatient 
admission or discharge) to ensure accurate medication regimens are communicated to 
accepting teams and to the patient. The same ambulatory EPIC note template that is 
used by the clinical pharmacist during the usual care visits will be utilized for 
documentation during these telehealth encounters.  EPIC is the inpatient and ambulatory 
EHR utilized within the study institution.    The process used to resolve medication safety 
issues during distant monitoring is outlined in Figure 4. Once the clinical pharmacist 
identifies an issue, they will develop a management plan using the algorithm detailed in 
Figure 5, discuss the recommendations with the providers, agree on a plan, and 
implement the plan with direct patient follow-up.  The algorithm in Figure 5 encompasses 
the major medication safety issues, including side effects, adherence, drug interactions 
and less than optimally controlled comorbid disease states.   
 

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This algorithm is a guideline, and the transplant pharmacist will use this, as well as their 
clinical judgment and professional experience, to develop the medication safety issue 
resolution plan. 
 
mHealth Medication Safety Monitoring and Management Tool:  Patients in the 
intervention cohort will have enhanced medication safety monitoring utilizing an 
integrated mHealth system, coalescing the EHR (EPIC) with an application developed by 
our research collaborative and FORACare telehealth systems to provide a seamless, 
bidirectional, patient-centered, home-based monitoring tool that will allow for early, 
effective and efficient identification of medication safety issues by the clinical transplant 
pharmacists. The application will provide patients a useful tool to conduct self-care 
monitoring and management, including timely reminders to take medications, automated 
messages when patients miss multiple medication doses, tracking of medication side 
effects and reporting trends in blood pressures and glucoses (when applicable).  Using 
our foundational research and through previous collaborations, we have partnered with 
Technology Applications Center for Healthful Lifestyles (TACHL) to incorporate 
monitoring tools and patient questionnaires that will minimize intrusions, while 
maximizing the potential of identifying medication safety issues, including medication 
errors, nonadherence and adverse drug events, early in their course.  Figure 6 lays out 
the conceptual diagram of this system, detailing how it will allow for the efficient creation 
and reconciliation of accurate medication regimens, while also monitoring medication 

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16
adherence and signs and symptoms of potential medication safety issues (medication 
errors or adverse drug events).   
 
   
 
 
Starting in the top left corner of Figure 6, the medication regimen is created or updated 
in the EHR by the transplant pharmacist or other qualified healthcare professional.  This 
data flows into the medication app (top middle of figure), through a continuity of care 
document (CCD), which contains machine-readable patient information.  The app 
accepts CCDs via direct messaging (government sponsored encrypted email), SFTP 
and FTPS. Upon receipt, the app parses the CCD and uses its data to create a patient 
friendly medicine schedule, where it is then updated and verified for accuracy by the 
transplant pharmacist. Once verified, the medication regimen flows into the patient’s 
mobile smartphone device (top right of figure).  Each medicine will include its purpose, 
route of administration, special instructions (e.g., “Avoid grapefruit and grapefruit juice”), 
possible side effects and adherence record.  The smartphone application allows the 
patient to have an accurate, updated list of their medication regimen, while also 
providing reminders to take medications at the correct times.  Medication reminders will 
include a checkbox for each medication. The patient will be asked to check the box if 

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they have taken that medicine. These self-reported responses get tabulated and 
recorded in the program as an adherence score for that medicine and an overall score 
for all medicines. As part of this study, the clinical pharmacist will have access to this 
data in the report dashboard, located on a secure HIPAA compliant website. If the 
patient changes or updates their medication regimen through the application, an email 
will be sent to the transplant pharmacist, who will contact the patient to determine the 
medication, dose and interval and review it as outlined in Figure 4. Once all issues are 
resolved, the pharmacist will enter the medication into the EHR as a self-reported 
medication. 
 
Home-based monitoring of blood pressures and glucoses, using the FORACare system, 
will also transfer into the application and the report dashboard.(42, 43)  The app will also 
give providers the ability to create and send surveys to the patient. The survey will 
populate on the patients’ home screen as an alert message. The alert message will not 
disappear until the survey has been filled out and submitted. Survey responses get 
recorded in the app and are incorporated into the report dashboard.  As part of this 
study, patients in the intervention cohort will receive medication side effect surveys 
during gaps in transplant clinic visits.  The survey was developed using the validated 
Memphis Medication Side Effect Survey, coupled with our formative research 
demonstrating which side effects are associated with the adverse drug events that are 
most commonly associated with hospital readmission.(44-46)  Patients will complete this 
survey and this data will then flow into the report dashboard for review as aggregate and 
trend information.  Thus, this mHealth system will allow both the patient and transplant 
pharmacist to track signs and symptoms of medication safety issues. 
3.b 
Method for Assigning Subjects to Treatment Groups  
Whether a patient is in the intervention group or the control will be by random selection 
using a random number generator in simple blocks of 8. 
3.c 
Subject Compliance Monitoring  
Monitoring for compliance with medications, clinic visits, blood pressure and glucose 
monitoring (if applicable) is a part of the intervention in the intervention cohort. If subjects 
are not complying with data monitoring in the intervention cohort, they will be contacted 
by the study pharmacist to encourage use of the smartphone and any relevant 
Bluetooth-enabled devices. If this does not resolve the noncompliance, the subject will 
be contacted by the study PI to discuss continued involvement in the study.  
These data will not be monitored real-time in the usual care cohort. Compliance with 
study data capture will be monitored by the study coordinators, who are completely 
independent of the pharmacists providing the interventions. They will gather data via 
direct subject interview and through review of the subject’s electronic medical records.  
3.d 
Blinding of Study Intervention 
This is an open-label study, so subjects and the research team will be aware of the study 
assignment. Due to the nature of the intervention, blinding of the subject and research 
staff is unable to be performed. In order to minimize bias, data for outcomes will be 
collected by blinded study personnel, as much as feasibly possible. 
 
 
 

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E 
Study Procedures  
 
E1 
Screening for Eligibility 
Adult (≥18 years old at the time of transplant) solitary kidney transplant recipients 6 to 36 
months post-transplant that meet study eligibility will be approached by research 
personnel for consideration for participation at the time of a usual care clinic visit or 
healthcare encounter with the transplant team. 
 
E2 
Schedule of Measurements 
 
All patients in both arms of the study will continue to receive usual post-transplant care.  
The supplemental care that is provided to the intervention group will all be via remote 
monitoring and televisits, also detailed in section above.  In addition, there will be two 
study specific clinic visits and four televisits that occur in all patients (both control and 
intervention arms), as detailed in the table below.  The Baseline visit will not be counted 
as a study visit, as this will be the usual care visit patients are identified, screened, 
consented and randomized at.  The table below outlines these visits and what will be 
assessed during the visits.   
 
Assessment 
Base-
line 
Month 
2 
Month 
4 
Month 
6 
Month 
8 
Month 
10 
Month 
12 
Obtain informed consent, 
collect baseline patient and 
transplant information 
X 
 
 
 
 
 
 
Assessment for medication 
errors 
 
 
 
X 
 
 
X 
Tele assessment for 
medication errors 
 
X 
X 
 
X 
X 
 
Assessment for adverse 
drug events 
 
 
 
X 
 
 
X 
Tele assessment for 
adverse drug events 
 
X 
X 
 
X 
X 
 
Assessment for health 
care encounters 
 
 
 
X 
 
 
X 
Tele assessment for 
adverse health care 
encounters 
 
X 
X 
 
X 
X 
 
Chart review assessment 
for acute rejection(s) 
X 
X 
X 
X 
X 
X 
X 
Chart review assessment 
for infection(s) 
X 
X 
X 
X 
X 
X 
X 
Chart review assessment 
for graft function, graft loss 
and death 
X 
X 
X 
X 
X 
X 
X 
 

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E3 
Safety and Adverse Events  
3.a 
Safety and Compliance Monitoring 
The data safety monitoring plan (DSMP) includes the use of a safety officer, with 
overarching IRB oversight, to monitor the study-related clinical outcomes, medication 
side effects, and adverse events.  Additionally, the DSMP will utilize the study statistician 
to review the data generated by the TRANSAFE Rx study and ensure data integrity. 
Summaries of adverse event reports and patient safety concerns raised by the safety 
officer will be made to the NIH in yearly progress reports unless the nature of a particular 
event is such that it bears reporting to the NIH immediately. The designated safety 
officer for the TRANSAFE Rx study is a well-experienced transplant physician who is not 
directly involved in the intervention component of the study. The designated statistician 
responsible for data oversight and creating the reports needed for the DSMP meetings is 
an experienced biostatistician with knowledge in monitoring clinical research data 
integrity.  
 
Both the safety officer and the biostatistician will coordinate data review and analysis 
and work closely with the study PI and the co-investigators. The functions of the 
designated safety officer are to: 1) provide scientific oversight; 2) review all adverse 
effects or complications related to the study; 3) monitor accrual; 4) review summary 
reports relating to compliance with protocol requirements; and 5) provide advice on 
resource allocation.  
 
The safety officer and statistician will meet at the following seven pre-designated study 
milestones: each time 34 patients have received at least six months of study follow-up 
care (four meetings), once 68 patients have completed the study (one meeting), once 
102 patients have completed the study (one meeting), and at study close-out. The team 
will also meet on an as needed basis for any unexpected serious adverse events or 
significant study findings. Data will be provided at these meetings by the investigators on 
key variables that may indicate harm, including significant medication safety events 
leading to hospitalization or intervention. Study patient clinical events, including 
hospitalizations, emergency room visits, acute rejections, life-threatening infections, graft 
loss and patient death will also be reviewed during these sessions. The biostatistician 
will evaluate confidentiality and integrity of the database, and the procedures for 
recording and storing confidential files. The safety officer will also review the elements of 
the research plan to deal with emergencies. At the conclusion of these meetings, the 
recommendations of the safety officer will be reviewed and the PI and co-investigators 
will take appropriate corrective actions as needed.  
 
The safety officer will have the authority to halt the trial if he/she perceives that harm is 
occurring due to the interventions.  
 
 

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3.b 
Medical Monitoring  
i 
Investigator only 
Investigators will monitor for serious adverse events and report them as indicated in the 
sections above. Additionally, adverse drug events and medication errors will be tracked 
as a study endpoint, with interim results reported as detailed in the DSMP. 
ii 
Independent expert to monitor 
The designated safety officer for the TRANSAFE Rx study is a well-experienced 
transplant physician who is not directly involved in the intervention component of the 
study. The functions of the designated safety officer are to:  1) provide scientific 
oversight; 2) review all adverse effects or complications related to the study; 3) monitor 
accrual; 4) review summary reports relating to compliance with protocol requirements; 
and 5) provide advice on resource allocation. The safety officer will have the authority to 
halt the trial if he/she perceives that harm is occurring due to the interventions. 
iii 
Institutional Data and Safety Monitoring Board 
The IRB will review and approve this clinical research protocol and patient consent 
forms, as well as have oversight for protection of patient privacy and safety, and monitor 
the study on an ongoing basis. Study-related severe adverse events will be reported to 
the IRB as they occur, if they were unexpected and deemed to be related to the study 
intervention. Annual reports to the IRB will indicate accrual rate, adverse events, new 
findings that may influence continuation of the study, and reports provided as part of the 
DSMP. 
iv 
Independent Data and Safety Monitoring Board 
The DSMP will review the data generated by the TRANSAFE Rx study.  Summaries of 
adverse event reports and any patient safety concerns raised by the safety officer will be 
made to the NIH/IRB in yearly progress reports unless the nature of a particular event is 
such that it bears reporting to the NIH/IRB immediately.  The designated statistician 
responsible for data oversight and creating the reports needed for the DSMP meetings 
will be an experienced biostatistician with knowledge in monitoring clinical research data 
integrity.  Both the safety officer and the biostatistician will coordinate data review and 
analysis and work closely with the study PI and the co-investigators The safety officer 
and statistician will meet at the following seven pre-designated study milestones:  each 
time 34 patients have received at least six months of study follow-up care (four 
meetings), once 68 patients have completed the study (one meeting), once 102 patients 
have completed the study (one meeting), and at study close-out. The team will also meet 
on an as needed basis for any unexpected serious adverse events or significant study 
findings.  Data will be provided at these meetings by the investigators on key variables 
that may indicate harm, including significant medication safety events leading to 
hospitalization or intervention.  Study patient clinical events, including hospitalizations, 
emergency room visits, acute rejections, life-threatening infections, CV events, graft loss 
and patient death will also be reviewed during these sessions.  The biostatistician will 
evaluate confidentiality and integrity of the database, and the procedures for recording 
and storing confidential files. The safety officer will also review the elements of the 
research plan to deal with emergencies.  At the conclusion of these meetings, the 
recommendations of the safety officer will be reviewed and the PI and co-investigators 
will take appropriate corrective actions as needed. 

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3.c 
Definitions of Serious Adverse Events and Adverse Drug Events 
 
Serious adverse events (SAEs) for this study are defined as hospitalizations, acute 
allograft rejections, graft losses and deaths that are unexpected and deemed to be 
directly related to the study intervention, as determined by the PI and reviewed during 
oversight in the DSMP reports.  All SAEs will be reported to the IRB as they occur.  
 
Adverse drug events (ADEs) will be defined according to the AHRQ Patient Safety 
Network, in which it describes an adverse drug event as “an adverse event (i.e., injury 
resulting from medical care) involving medication use.(21) The severity of the adverse 
drug event will be defined according to a modified version 4.0 of the CTCAE developed 
by the National Cancer Institute.   The CTCAE is a standardized classification system 
developed to assess the frequency and severity of adverse events.  It was originally 
designed for cancer patients, but is now routinely utilized across multiple patient types in 
clinical research.(48, 49) The modified CTCAE utilized by the study investigators for this 
study can be found at the end of this document.  ADEs will be summarized in DSMP 
reports and categorized by severity and study arm.  These reports will be provided to the 
IRB on an annual basis. 
3.d 
Classification of Events 
Adverse drug events will be classified according to the modified CTCAE, as detailed 
above. 
3.e 
Data Collection Procedures for Serious Adverse Events and Adverse Drug 
Events 
In both the usual care and intervention arms, a highly trained clinical research 
coordinator will independently interview all participants at bimonthly intervals to capture 
and record all medication errors and adverse drug events, including timing, likely cause 
and severity of each event.  These events will be further reviewed and adjudicated by a 
pharmacist not involved in delivering the study intervention, in a blinded fashion.  To 
assess for medication errors, the research coordinator will review and compare the 
patient’s documented medication regimen in the electronic health record (the regimen 
intended to be taken) to the medication regimen actually being taken by the patient, 
which will be assessed using the patient’s medication bottles and/or lists.   
 
Serious adverse events will be continuously screened for by chart review for new 
hospitalizations, kidney biopsies, and deaths.  The EHR will be utilized, as it has alerting 
systems capable of screening and notifying the study coordinator and PI of events within 
study patients. 
 
To assess for adverse drug events, the research coordinator will review patient 
symptomology, vital signs and laboratory values.  The research coordinator will be 
trained by the study pharmacists in identifying medication errors and adverse drug 
events, determining causality and grading the severity.  To ensure objectivity and 
consistency in recording these events across both study cohorts, a number of 
safeguards will be instituted.  First, the study investigators will utilize the same research 
coordinator to record all medication errors and adverse drug events.  Second, this 
research coordinator will be completely independent of the telehealth intervention that is 
being performed and will be blinded to the patient’s randomized group.  Third, only the 
medication errors and adverse drug events recorded by this research coordinator will be 

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used for data analysis. Finally, these patient assessments will be followed by an 
independent assessment by a clinical transplant pharmacist that is not associated with 
delivering the study intervention. This will ensure that event rates are not biased towards 
a higher capture rate in the intervention cohort, which will be receiving more intense 
scrutiny of their medication regimens by a clinical pharmacist. 
 
E4 
Study Outcome Measurements and Ascertainment 
The primary outcome measure of this study will be the incidence and severity of 
medication errors and adverse drug events, which will be identified, categorized and 
compared between the intervention and control cohorts as detailed above and in the 
following sections.  The exploratory outcome measures of this study are to compare the 
incidence and severity of acute rejections, infections, graft function, graft loss and death 
between research cohorts and measure the association between medication safety 
issues and these events.  Demonstrating improvements in acute rejections, infections, 
graft loss or death within the intervention group will provide the data needed to design a 
larger, multicenter study (through dissemination efforts detailed at the end of this 
proposal).  Additional data that will be gathered includes patient surveys to capture 
measures of sociodemographics, health literacy, depression, social support and trust.  
These are important variables that may modify or confound the impact of the 
intervention. 
 
Study endpoint definitions and assessment plan:   
The following will be used to define and capture data and events within this study: 
 
1. 
Medication errors will be defined as documentation that a patient is taking a 
medication in a manner that was not intended; synonymous with the definition developed 
by Overhage and utilized within our previous research.(11,14).  
 
2. 
Adverse drug events will be defined according to the AHRQ Patient Safety 
Network, in which it describes an adverse drug event as “an adverse event (i.e., injury 
resulting from medical care) involving medication use”.(21) The severity of the adverse 
drug event will be defined according to a modified version of the CTCAE developed by 
the National Cancer Institute and utilized in our previous research.   The CTCAE is a 
standardized classification system developed to assess the frequency and severity of 
adverse events.  It was originally designed for cancer patients, but is now routinely 
utilized across multiple patient types in clinical research.(48, 49).  In both the usual care 
and intervention arms, a highly trained clinical research coordinator will independently 
interview all participants at bimonthly intervals and review their medical records to 
capture and record all medication errors and adverse drug events, including timing, likely 
cause and severity of each event.  To assess for medication errors, the research 
coordinator will review and compare the patient’s documented medication regimen in the 
electronic health record (the regimen intended to be taken) to the medication regimen 
actually being taken by the patient, which will be assessed using the patient’s medication 
bottles.  To assess for adverse drug events, the research coordinator will review patient 
symptomology, vital signs and laboratory values.  Prior to the study being opened for 
enrollment, the research coordinator will be extensively trained by the study pharmacists 
in identifying medication errors and adverse drug events, determining causality and 
grading the severity.   
 

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3. 
Acute rejection will be defined as a renal allograft biopsy demonstrating at least 
grade 1A rejection by Banff ’97 criteria or higher or treated borderline rejection.(50) All 
patients will be required to have biopsy confirmation of rejection episodes within 24 
hours of onset of treatment for acute rejection, as per our protocol and usual.  It is 
standard care that all kidney allograft biopsies performed for transplant recipients occur 
at the transplant center (study institution).  Biopsies will be read by the local pathologist, 
as usual care.  This pathologist will not be informed of participant participation in the 
study and will be blinded to cohort assignment.  The study coordinator capturing clinical 
event data, different from the coordinator capturing medication error and adverse drug 
event data (to ensure blinding is maintained), will review the medical record at regular 
intervals to determine the incidence, timing, severity, treatment regimen and reversibility 
of each acute rejection episode for all study participants. 
 
4. 
Infections will be defined as any diagnosed and treated infection, and will be sub-
classified as bacterial, viral, or fungal etiologies. Flu-like illnesses and viral syndromes 
NOT requiring antimicrobial therapy will not be defined as infections for this study.   
Opportunistic infections will also be sub-classified for this study as viral, bacterial or 
fungal and defined as infections not seen in immunocompetent individuals; the most 
common opportunistic infections in kidney transplant recipients include CMV, BK, EBV 
and candidiasis.(51, 52)  The study coordinator capturing clinical event data, different 
from the coordinator capturing medication error and adverse drug event data (to ensure 
independence is maintained), will review the medical record at regular intervals to 
determine the incidence, timing, severity, treatment regimen and cure timing of each 
infection episode for all study participants.   
 
5. 
Graft function will be defined using the 4-variable MDRD equation to estimate 
GFR.  This equation has been validated as an accurate reflection of true GFR within 
kidney transplant recipients.(53) Routine serum creatinine concentrations, which are 
measured as part of usual care, will be utilized to estimate GFR at these approximate 
time points:  baseline, 3, 6 and 12 months post-enrollment.   
 
6. 
Graft failure will be defined as return to chronic dialysis, transplant nephrectomy, 
retransplantation or death.  The study coordinator capturing clinical event data, different 
from the coordinator capturing medication error and adverse drug event data (to ensure 
independence is maintained), will review the medical record at regular intervals to 
determine if a study patient has developed graft failure.  The timing and cause of each 
graft loss will be recorded for comparative analysis.  Patient death will also be captured 
in a similar fashion, with timing and cause recorded as well. 
 
7. 
Healthcare encounters will be defined as any direct encounter (face-to-face) 
between the study patient and a physician or advance practice provider (APP) occurring 
within a licensed healthcare facility and occurring during the 12-month study.  These 
encounters will be categorized as ambulatory clinic visits, ambulatory procedure visits, 
acute care/emergency room visits and hospitalizations.  Hospitalizations will be defined 
as an admission to a hospital with at least one overnight stay.  Length of stay within the 
hospital for readmissions will also be captured.  Healthcare encounters will be captured 
through direct study subject interviews with patients at bimonthly intervals.(36)  The 
study coordinator will record all healthcare encounters that have occurred.  If the patient 
has a health care encounter outside of the study institution, the research coordinator will 
document the type of encounter to estimate costs, as detailed below.   
 

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8. 
Costs associated with care will be assessed based on data from hospital 
accounting at the study institution, once the study is completed.  Costs will be measured 
from the time of randomization up until the end of the 12-month follow-up period.  
Analyses will include all costs associated with inpatient and outpatient care, including 
hospitalizations, ambulatory care visits, ambulatory procedure visits, acute 
care/emergency room visits and laboratory assessments.  Costs uniquely associated 
with the intervention group will include the costs of the devices and data plan provided to 
the patients, time necessary for training patients on use of the technology and research 
pharmacist time associated with the intervention. Total costs will be calculated for each 
cohort.  These data will be electronically captured by providing a list of patient’s MRNs to 
hospital accounting after the completion of the study to allow for accurate and complete 
billing information to accrue.  Costs associated with healthcare encounters that occur 
outside the study institution will be estimated by acquiring information from the patient 
regarding the type of encounter and using this data to estimate cost based on 
cost/charge ratios from the study institution.    This will be a costs - consequences 
analysis (CCA)] using cost effectiveness methodology, taken from the societal 
perspective. 
 
F 
Statistical Plan  
F1 
 Sample Size Determination and Power 
Based on previous studies conducted by our research collaborative, we estimate that 
approximately 64% of kidney transplant recipients in the control group will experience a 
medication error during the one year study (defined using the Overhage criteria).(1, 2)  
Our previous research demonstrates that pharmacist-led initiatives can reduce these 
medication errors by approximately 50%.(3, 4)  Using these estimates, enrolling 104 
participants (52 in each cohort), will provide 92% power in detecting a statistically 
significant difference in medication error event rates, with a two-tailed α=0.05.  We will 
also have 94% power (two-tailed, α=0.05) to detect a 33% reduction in significant 
adverse drug events (CTCAE grade 3 or higher), given an estimated incidence rate of 
87% in the control cohort and the strong association between medication errors and 
adverse drug events.(2, 5)  From previous analyses, we expect that the control cohort 
will have a mean of 18.4±2.6 healthcare encounters (clinic visits, acute care/ER visits 
and hospitalizations), during the one year study.  We estimate the intervention group will 
see an 8% absolute reduction in total encounters, to a mean 17.0 encounters, with an 
estimated 33% relative reduction in the mean number of hospital readmissions (1.2 vs. 
0.8, respectively).(2)  Given these estimates (two-tailed, α=0.05), enrolling 52 patients in 
each arm will provide 80% power to detect a statistically significant difference.  It is 
estimated that the intervention will also produce a mean cost savings of at least $2,489 
per patient ($7,658 in the control cohort and $5,169 in the intervention cohort, with σ 
estimated at $4,530).(2)  This study is expected to have >80% power to detect a 
statistically significant difference in total post-transplant costs between cohorts, given 
these estimates. 
 
For the exploratory outcomes of acute rejection, infections, graft function, graft loss and 
death, this study is not powered to detect statistically significant differences in these 
clinical events between groups.  However, we expect to demonstrate meaningful clinical 
signals, particularly with a reduction in acute rejection.  Our previous study demonstrated 
an acute rejection rate that was 1.8 times higher in patients experiencing a significant 
medication error (13.7% vs. 7.7%, respectively).(2)  Thus, we expect an overall acute 
rejection rate of 12% in the control cohort and 9% in the intervention cohort, 

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corresponding with a 25% relative reduction in acute rejection rates.   Based on previous 
randomized controlled trials conducted within the study institution, we expect to maintain 
an 85% retention rate.(6)  We will adjust our total sample-size to 136 patients (68 in 
each cohort) to account for dropouts, thus maintaining adequate sample-size to produce 
at least 80% power to detect statistically significant differences in the primary outcome 
measures. 
 
F2 
 Interim Monitoring and Early Stopping 
The safety officer and statistician will meet at the following seven pre-designated study 
milestones:  each time 34 patients have received at least six months of study follow-up 
care (four meetings), once 68 patients have completed the study (one meeting), once 
102 patients have completed the study (one meeting), and at study close-out. The team 
will also meet on an as needed basis for any unexpected serious adverse events or 
significant study findings.  Data will be provided at these meetings by the investigators 
on key variables that may indicate harm, including significant medication safety events 
leading to hospitalization.  Study patient clinical events, including hospitalizations, 
emergency room visits, acute rejections, life-threatening infections, graft loss and patient 
death will also be reviewed during these sessions.  The biostatistician will evaluate 
confidentiality and integrity of the database, and the procedures for recording and storing 
confidential files. The safety officer will also review the elements of the research plan to 
deal with emergencies.  At the conclusion of these meetings, the recommendations of 
the safety officer will be reviewed and the PI and co-investigators will take appropriate 
corrective actions as needed. 
 
The safety officer will have the authority to halt the trial if he/she perceives that harm is 
occurring due to the interventions. 
 
F3 
 Analysis Plan 
This analysis will incorporate the intent-to-treat principle, namely, all randomized 
participants will be included in the analysis according to their intervention assigned at 
baseline.  The two groups will be compared using standard statistical analyses.  Data 
will be reported using percentages for nominal and ordinal variables and compared 
using Fisher’s exact test or Pearson’s chi-squared test as appropriate.  This includes 
baseline demographic and transplant characteristic variables, as well as the outcome 
variables of the incidence and severity of medication errors and adverse drug events, 
acute rejection and infections.  For continuous variables with normal distribution, results 
will be reported using means and standard deviations with statistical comparison using 
Student’s t-test for two independent samples.  For non-normally distributed variables, the 
results will be reported using medians and interquartile ranges, with statistical 
comparison conducted using the Mann Whitney U test.  Normal distribution of 
continuous variables will be assessed using normality plots and the Shapiro-Wilk test.  
Normal variance will be assessed using Levene’s test for equality of variances.  Results 
for graft and patient survival will also be reported using Kaplan-Meier survival curves and 
compared using the Log Rank test. 
 
If it is determined that there are significant imbalances in baseline demographics or 
characteristics known to influence any of the outcome measures, multivariable modelling 
will be used to adjust for these differences.  For nominal outcomes, binary logistic 
regression will be used in a standard entry fashion, which will include both the grouping 
variable and all known risk-factors.  For continuous outcomes that demonstrate linearity 

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in the relationship between dependent and independent variables, with a lack of serial 
correlation between covariates, homoscedasticity of the errors and normality of the error 
distribution, linear regression will be utilized in a similar manner.  We will adjust for 
baseline values if the interventions are discrepant at baseline. This model will include the 
intervention arm and baseline response as fixed-effects and is known to lead to very 
precise inference.(7)  If any of the four aforementioned assumptions are violated, then 
the data variables will either be transformed or appropriate substitute multivariable 
modelling will be used.  Cox proportional hazard regression analysis will be used for 
time-dependent survival analyses involving the outcomes of graft and patient survival.  
For count outcomes, such as health care encounters, we will use Poisson regression; if 
the assumption of equal mean and variance is violated (over dispersion), we will use 
Negative Binomial regression. In all models, we will adjust for correlation of outcomes by 
including random effect terms. For all models that belong to the generalized linear model 
(linear, logistic, Poisson), we will use generalized estimating equations (GEE), and for 
survival outcomes, we will use frailty Cox regression.(8)  We will use multiple imputation 
techniques to deal with missing data that is at random (MAR).(9)  MAR assumes that the 
probability that an outcome is missing depends on observed outcomes. While 
mechanisms for missingness are likely to be MAR, we will also do sensitivity analysis for 
data missing not at random (MNAR) using methods from Little and Rubin.(9) 
F4 
 Statistical Methods  
The two groups will be compared using standard statistical analyses.  Data will be 
reported using percentages for nominal and ordinal variables and compared using 
Fisher’s exact test or Pearson’s chi-squared test as appropriate.  This includes baseline 
demographic and transplant characteristic variables, as well as the outcome variables of 
the incidence and severity of medication errors and adverse drug events, acute rejection 
and infections.  For continuous variables with normal distribution, results will be reported 
using means and standard deviations with statistical comparison using Student’s t-test 
for two independent samples.  For non-normally distributed variables, the results will be 
reported using medians and interquartile ranges, with statistical comparison conducted 
using the Mann Whitney U test.  Normal distribution of continuous variables will be 
assessed using normality plots and the Shapiro-Wilk test.  Normal variance will be 
assessed using Levene’s test for equality of variances.  Results for graft and patient 
survival will also be reported using Kaplan-Meier survival curves and compared using 
the Log Rank test. 
 
F5 
 Missing Outcome Data 
We will use multiple imputation techniques to deal with missing data that is at random 
(MAR).(9)  MAR assumes that the probability that an outcome is missing depends on 
observed outcomes. While mechanisms for missingness are likely to be MAR, we will 
also do sensitivity analysis for data missing not at random (MNAR) using methods from 
Little and Rubin.(9) 
F6 
 Unblinding Procedures  
No unblinding procedures are necessary, as this is as open-label study. 
 

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G 
Data Handling and Record Keeping  
G1 
Confidentiality and Security 
In order to protect subjects against any risk regarding loss of personal information, all 
obligations under the Health Portability and Accountability Act (HIPPA) will be met.  
Additionally, all data will be collected and stored through the secure network server and 
behind the MUSC firewall.  We will use electronic CRF forms to gather all study 
information (redcap.musc.edu).  Data will only be stored on campus computers under 
the MUSC secure network.  Data collection forms will be maintained within an office, 
which is a locked office facility on campus.  Only approved study members will have 
access to patient data.   
 
Any data or information shared for dissemination will be de-identified and the 
confidentiality of all participants will be strictly maintained.  The only persons with access 
to protected health information (PHI) will include study investigators, research 
coordinators and those approved by the MUSC IRB.  All data will be secured on MUSC 
servers, behind firewalls, with passwords protecting entry in these systems.  All PHI will 
be obtained and managed in accordance with the HIPAA Privacy Rule (45 CFR Parts 
160 and 164). 
G2 
Training  
The intervention pharmacists will participate in a thorough training session with the 
TACHL group and PI. During this training, the dashboard’s functionality will be reviewed, 
along with the standard operating procedure manual which fully guides interventions.  
Pivotal sessions that occur during this conference will include:  review of dashboard 
specifics, alert functions using the dashboard, assessing clinical relevance of alerts, alert 
categories, interventions to address alerts, clinical and research documentation, and 
provider collaboration mechanisms.  The investigational team will lead these sessions to 
deliver the presentations.   
 
Research coordinators will also be thoroughly trained by the investigational team on 
assessing and documenting medication errors, adverse drug events and clinical 
outcomes.  Detailed algorithms will be provided to the study coordinators to assist with 
these assessments and documentation, to ensure study fidelity. In addition, the 
pharmacist conducting the adjudication of these events will also be trained to ensure that 
the assessments and documentation of events are consistent across all individuals. 
 
Before the study is opened for recruitment, a site initiation visit (SIV) will occur whereby 
all transplant clinical personnel will be invited and the study specifics will be presented.  
This, along with regular emails to the transplant group, will ensure that the study is well 
understood by both clinical and research personnel prior to initiation. 
 
H 
Study Administration 
H1 
Organization and Participating Centers 
The Medical University of South Carolina will be the only participating center. 

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H2 
Funding Source and Conflicts of Interest 
The study is funded by AHRQ. None of the investigators have any conflicts of interest 
related to this study. 
H3 
Committees 
There is one group formed specifically for the conduct of this study, which is the DSMC.  
The DSMC will consist of the PI, co-investigators, study coordinator, statistician, data 
manager and consultants on the proposal. The functions of the DSMC will include: 1) 
providing scientific oversight; 2) reviewing all serious adverse events (adverse drug 
events, graft loss and death events, compared across intervention groups) or 
complications related to the study; 3) monitoring site adherence to the intervention; 4) 
reviewing summary reports relating to compliance with research protocol requirements; 
and 5) providing advice on resource allocation. The DSMC will meet according to the 
safety monitoring plan (Section 4.b.iv) and as necessary by telephone or in person. The 
recommendations of the DSMC will be reviewed and the PI will take appropriate 
corrective actions as needed. The intervention clinical pharmacists group will include the 
clinical pharmacists that were assigned to the intervention arm of the study.  During the 
study, this group will have monthly meetings to discuss the intervention, identify and 
resolve study related issues and discuss pertinent study-related materials. 
H4 
Subject Stipends or Payments  
Patients will be paid $50 for each study visit, not including the baseline visit, which will 
occur during a usual care visit.  Thus, if patients complete the 12-month study, they will 
be remunerated $100 total, which is provided to cover travel and parking costs 
associated with the study visits. 
H5 
 Study Timetable 
The target dates for major milestones are detailed below.  We expect to complete this 
trial and present final results within 36 months, based on the following: 
• 
IRB submission:  Target of July 31, 2017 
• 
IRB approval:  Target of August 31, 2017 
• 
Technology development and testing complete: Target of September 30, 2017 
• 
Study Open for Recruitment: Target of October 15, 2017 
• 
Expected Enrollment by June 30, 2018: Target of 68 patients enrolled 
• 
Last Patient Enrolled:  Target of March 31, 2019 
• 
Expected Enrollment by June 30, 2019: Target of all 136 patients enrolled, with 
68 completed the study 
• 
Last Patient, Last Visit: Target of March 31, 2020 
• 
Complete Data Analysis:  Target of April 30, 2020 
• 
Begin to Make Technology Available to Other Pharmacists Managing Non-
Transplant Patients:  Target of Spring 2020 
• 
Present Final Results at National Meeting (American Transplant Congress, 
ACCP):  Target of May and June 2020 
• 
Present Results to AST Transplant Pharmacy COP:  Target of June 2020 
• 
Complete Final Write-Up and Manuscript Submissions:  Target of June 30, 2020 
I 
Publication Plan  
 
Planned publications include submissions to the following potential journals: 

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1) 
American Journal of Transplantation 
2) 
Drug Safety 
3) 
Health Technology Assessment 
4) 
Journal of Medical Internet Research 
5) 
American Journal of Kidney Diseases  
6) 
Journal of the American Society of Nephrology  
7) 
Clinical Journal of the American Society of Nephrology  
8) 
Kidney International 
9) 
Journal of the American Medical Association 
10) 
Annals of Internal Medicine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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J 
 Attachments  
 
 
Screenshots of the mHealth app and web-based portal to manage medications 
and med adherence 
 
Welcome page to the web-based portal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Page to manage patients 
 
  
Page to manage medications for a specific patient 
 
 
 
 
 
 

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Page to manage medication scheduling for a specific patient 
 
  
Display of regimen schedule for patient to view or to print off for a hardcopy 
 
 
 
 
 
 
 

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Screenshots of the mHealth app demonstrating how the medication regimen is displayed 
 
 
 
  
 
 
 
 
 

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Screenshots of the mHealth app demonstrating how the medication schedule is 
displayed 
 
 
 
Screenshots of the mHealth app demonstrating how the medication adherence reporting 
function is displayed 
 

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K 
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