A Prospective, Randomized, Multicenter, Open-Label, Pilot Study to Investigate Medication Adherence & Patient Reported Symptom Occurrence & Interference w/ Daily Life Comparing Envarsus XR® & Immediate Release Tacrolimus in Adult Renal Transplant Recipients (SIMPLE)
Phase: PHASE4
Conditions: Kidney Transplant Recipients
Sponsor: Mayo Clinic

 
 
A Prospective, Randomized, Multicenter, Open-
Label, Pilot Study to Investigate Medication 
Adherence & Patient Reported Symptom 
Occurrence & Interference w/ Daily Life 
Comparing Envarsus XR® & Immediate Release 
Tacrolimus in Adult Renal Transplant Recipients 
(SIMPLE)   
 
NCT03979365 
 
08April2021 

Clinical Study Protocol [#SIMPLE] 
 
Page 1 of 35 
 
CLINICAL STUDY PROTOCOL  
 
A Prospective, Multicenter, Open-Label, Observational Pilot Study to Investigate Medication Adherence 
and Patient Reported Symptom Occurrence and Interference with Daily Life Comparing Once-Daily 
Envarsus XR® and Twice-Daily Immediate Release Tacrolimus in Adult Renal Transplant Recipients 
(SIMPLE) 
 
 
Clinical Coordination & Data Management  
 
Mark Stegall, M.D.  
Principal Investigator – Lead Site 
Multicenter Transplant Alliance – Director 
Department of Surgery and Immunology 
Mayo Clinic  
Rochester, MN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Version: 3.0 
Date: 08APR2021 
 

Clinical Study Protocol [#SIMPLE] 
 
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Participating Centers of the Multicenter Transplant Alliance (MTA) 
 
Henry Ford Hospital 
Investigators: Dean Kim, M.D. and Millie Samaniego, M.D. 
 
Mayo Clinic Arizona 
Investigator: Raymond Heilman, M.D. 
 
Mayo Clinic Jacksonville 
Investigator: Martin Mai, M.D. 
 
Mayo Clinic Rochester  
Investigators: Mark Stegall, M.D. and Carrie Schinstock, M.D. 
Biostatistician: Byron Smith, Ph.D., M.S. 
 
Terasaki Research Institute (TRI)  
Investigators: Matthew Everly, Pharm.D. and Jennifer Beaumont, M.S.  
 
Washington University St. louis 
Investigators: Massini Merzkani, M.D. and Tarek Alhamad, M.D, M.S. 
 
 
 

Clinical Study Protocol [#SIMPLE] 
 
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SYNOPSIS 
Title: A Prospective, Multicenter, Open-Label, Observational Pilot Study to Investigate Medication 
Adherence and Patient Reported Symptom Occurrence and Interference with Daily Life Comparing 
Once-Daily Envarsus XR® and Twice-Daily Immediate Release Tacrolimus in Adult Renal Transplant 
Recipients (SIMPLE) 
 
Name of Products Studied: Envarsus XR® and tacrolimus (twice daily formulation) 
 
Study Center(s): Multicenter Transplant Alliance – Kidney Centers   
 
Study Design: Prospective and observational  
 
Study Period (years): 
 
Estimated date of first subject enrolled: May 2019 
Estimated date last subject to complete the study (12 month follow-up): May 2021 
 
Enrollment Rationale: The Multicenter Transplant Alliance Kidney Consortium collectively transplants 
more than 1,500 people each year (10% of the total number of kidney transplants in the United States 
annually). Approximately 60% of these patients will be eligible for this study. We consider a 12 month 
enrollment time to be a conservative estimate.  
 
Study Background:  
 
Despite improvement in short-term graft outcomes in organ transplant, transplant patients still have to 
take on complex medication regimens to achieve current results. Adherence to these complex medications 
is an important problem in light of the potential risk of acute and chronic rejection and the associated 
burden of increased hospitalization, cost, and diminished quality of life that results from missed doses and 
poor overall drug taking. Part of the diminished quality of life is also tied to the bothersome symptoms 
patient feel after transplant. Most patients experience symptoms that relate to either the overall transplant 
immunosuppression or medication specific side effects. In the BENEFIT and BENEFIT-EXT trials, 
>60% of patients reported tiredness and lack of energy as an issue 1. Sleep problems, mood swings, 
restlessness, anxiety, depression, and concentration and memory difficulties appeared in approximately 
50-60% of patients. In addition to these symptoms, >38% patients also reported numerous others side 
effects that have been strongly associated with calcineurin-inhibitors such as tacrolimus that include 
dizziness, muscle cramps, trembling hands, tingling in hands and feet, and headache.  
 
Study Rationale:  
 
We hypothesize that the use of once-daily Envarsus XR® leads to a decrease in some transplant- and 
tacrolimus-related adverse symptoms and potentially leads to improvement in quality of life and 
medication adherence when compared to twice-daily tacrolimus. In order to assess this hypothesis, a 
prospective, multi-center, open-label, observational, pilot study to investigate medication adherence and 
patient reported symptom occurrence and interference with daily life comparing once-daily Envarsus 
XR® and twice-daily immediate release tacrolimus in adult renal transplant recipients (SIMPLE) is being 
proposed.  
 
The primary objective of this study is to compare tacrolimus formulations (Envarsus XR® versus twice a 
day tacrolimus) with the hypothesis that Envarsus XR® improves transplant- and tacrolimus- associated 
symptoms when compared to a twice a day tacrolimus regimen. In addition, as part of this study, 

Clinical Study Protocol [#SIMPLE] 
 
Page 4 of 35 
 
adherence, additional patient reported outcomes (PROs), patient satisfaction, and health related quality of 
life (HRQoL) will be measured. There is currently a limited amount of data available describing the side 
effects/symptoms that are most important (i.e. occur most often and are poorly tolerated) to transplant 
patients taking tacrolimus immunosuppression. These symptoms/side effects could clearly impact 
medication adherence. Furthermore, no data currently exists as to how these symptoms/side effects relate 
to adherence, quality of life, and patient satisfaction. This study will assess the correlation between 
adherence, PROs, patient satisfaction, and health related quality of life (HRQoL). It is also possible that if 
the increase in adherence is large enough; there could be a sufficient change in long-term patient risk for 
antibody mediated injury and subsequent decrease in hospitalization and cost. 
 
Study Design Rationale: 
 
Patients will be enrolled into the study within the first 30 days post-transplant. Treatment will not be 
determined by this protocol, and there is no intervention. The treatment decision will be made by each 
patient’s transplant care team, independent of the study.  
 
For the primary objective, comparison of calcineurin inhibitor related symptoms, a standard two-group 
design will be used to compare treatment groups. These groups will also be compared for transplant-
related symptoms, health-related quality of life, adverse events, patient satisfaction, adherence, and graft 
function. 
 
Products Studied:  
 
• 
Tacrolimus (twice daily immediate release (IR) oral formulation) or  
• 
Envarsus XR® (a once daily extended-release oral tacrolimus formulation).  
 
Envarsus XR® is an FDA approved medication and is indicated for the prevention of organ rejection in 
de novo kidney transplant patients in combination with other immunosuppressants.  
 
Primary Objective: The primary objective of the study is to determine if patients taking Envarsus XR® 
report fewer of the side effects that are commonly associated with calcineurin-inhibitor therapy than 
subjects taking tacrolimus immediate release twice daily.   
 
Primary Endpoint:  Difference in mean calcineurin inhibitor-related symptoms severity score at 12 
months post- kidney transplantation in the Envarsus XR® group vs immediate-release, twice-daily 
tacrolimus group.   
The CIRS is a questionnaire that assesses five symptoms (from PRO-CTCAE) that have been shown to be 
associated with calcineurin inhibitors. These symptoms include trembling hands, muscle cramps, muscle 
weakness, swollen gums, and increased hair growth. Each symptom is based on symptom severity in the 
last 7 days scaled from 0 (none) – 4 (very severe). The cumulative score ranges from 0-20. Based on 
internal data, we expect a mean CIRS score in the control group (immediate release tacrolimus) to be 
around 3.8 +/- 3.6 and hypothesize a 30% reduction in the Envarsus XR® group. This reduction is 
equivalent to a 1 point difference on the 0-20 scale or a standardized effect size (mean difference / 
standard deviation) of 0.29.  
 
 
 

Clinical Study Protocol [#SIMPLE] 
 
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Secondary Endpoints: 
 
1. Reduction in the population mean of any one of the five individual CIRS item including:  
trembling hands, muscle cramps, muscle weakness, swollen gums, and increased hair growth 
between the two treatment groups at 12 months 
2. Total percent of patients in each treatment group with a severe or very severe score (3 or 4) on 
any CIRS item 12 months. 
3. Total percent of patient with a reduction in a CIRS item score from a severe or very severe score 
(3 to 4) to a mild to moderate (1 or 2) score from 4 to 12 months.  
4. Total percent of patients with a reduction in any single CIRS item by 1 point or greater from 4 to 
12 months.  
5. Difference in mean transplant-related symptoms (TRS) score between treatments at 12 months 
post-transplant.  
The TRS is a multi-item questionnaire capturing 15 symptoms (from PRO-CTCAE) that have 
been shown to be associated with transplant and general health-related quality of life 
improvement. These symptoms include change in taste, constipation, diarrhea, swelling in arms 
or legs, palpitations, dry skin, darkening of skin, blurry vision, headache, insomnia, anxiety, 
sadness, discouraged, increase in appetite, and fatigue. Each symptom is based on symptom 
severity in the last 7 days and scaled from 0 (none) – 4 (very severe). Some symptoms also have 
added questions pertaining to frequency and/or interference with daily activities. The sum of the 
severity score ranges from 0-60. The improvement in transplant symptoms will be measured by 
the difference between treatment groups in the mean TRS score. 
 
6. Improvement in health-related quality of life (HRQoL), as measured by the PROMIS-29 health 
profile, will be compared between groups at 12 months post-kidney transplantation. The 
PROMIS-29 produces scores for depression, anxiety, fatigue, pain interference, sleep disturbance, 
physical function, participation in social roles, and pain intensity. Physical and mental health 
summary scores will also be calculated.  
 
Standardized effect sizes (mean difference / standard deviation) for differences in HRQOL 
(PROMIS-29) scores will be calculated to compare twice daily immediate release tacrolimus oral 
to Envarsus XR®.  
 
7. Improvement in individual symptoms captured in the TRS questionnaire will be compared.  
The standardized effect size (mean difference / standard deviation) on TRS score will be 
calculated and compared between treatments. Individual TRS items will be classified as 
improved, worsened, unchanged and compared between treatments. 
  
8. Improvement in overall tolerability or patient bother due to side effects, measured by item GP5 
(“I am bothered by side effects of treatment”) from the FACT-G.  
Patients’ GP5 responses will be classified as improved, worsened, or unchanged and compared 
between treatments. 
 
9. Improvement in mean taking adherence, defined as the percent of prescribed doses taken each 
day (as measured by electronic monitoring), rates between groups.  

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The assumption is that the mean taking adherence will 75% for the twice-daily immediate release 
tacrolimus and 90% for the Envarsus XR® (and standard deviations of 38% and 30%, 
respectively).  
 
10. Improvements in patient medication satisfaction as assessed by Transplant Satisfaction 
Questionnaire for Medication (question 14) at 12 months post-transplant. 
Responses to the Transplant Satisfaction Questionnaire for Medication (question 14) will be 
compared between twice daily immediate release tacrolimus oral and Envarsus XR®. 
 
11. Correlation between de novo DSA (dnDSA, collected as part of standard of care in MTA-K) and 
degree of taking and timing adherence.  
Proportion of patients at different adherence thresholds (>70% vs ≤70%, >80% vs ≤80%, >90% 
vs ≤90%, and 100% vs below 100%) of taking and timing adherences between 4 months and 12 
months post-transplant will be correlated with the presence or absence of dnDSA by 12 months 
post-transplant.   
 
12. Safety and tolerability of Envarsus XR, as measured by incidence of adverse events (AEs), 
changes in clinical safety labs, and hospitalizations.  
 
Difference between treatment groups in safety parameters including the incidence of adverse 
events (AEs), changes in clinical safety labs, and hospitalizations. 
 
Inclusion criteria  
 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
• 
Patient is an adult (18 years of age or older). 
• 
Treatment with Envarsus XR® or immediate-release, twice-daily tacrolimus has been indicated 
by patient’s transplant care team.   
• 
Patient is a recipient of a deceased or living donor kidney transplant. 
• 
Patient is able to comply with study procedures for the entire length of the study. 
• 
Patient has been informed about the study survey and has signed an informed consent form. 
 
Exclusion criteria  
 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:  
• 
Patient is unable or unwilling to complete study patient reported outcome questionnaires. 
• 
Patient is currently receiving azathioprine 
• 
Patient is currently receiving an mTOR inhibitor (sirolimus, everolimus) 
• 
Patient is currently receiving belatacept 
• 
Patient has received investigational immunosuppression 1 month prior to transplant or post-
transplant 
• 
Patient is in a setting where a professional care taker is responsible for dispensing subject’s 
medication.   
 
Study Duration 
 
Following enrollment, each patient will be maintained in the study for 12 months.  

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Number of Patients 
 
A total of 240 patients will be enrolled for the study. The enrollment will occur over a 12 month period. 
The average monthly enrollment will be 20 patients per month. 
 
Study Design and Methodology 
 
This is a prospective, multi-center, open-label, observational study comparing transplant-specific patient 
reported outcomes and medication adherence between Envarsus XR® and immediate release tacrolimus 
medication in adult renal transplant recipients. The study will enroll 240 patients and survey these patients 
at baseline (first 30 days post-transplant), at 4 months, and at 12 months post-transplantation.  
 
Study Method 
 
• 
Adverse Events: During the entire study period, each patient will be monitored at least monthly 
for trough blood levels, and undergo safety and adverse event assessments as per standard of care. 
The patient will be followed as appropriate to maintain the tacrolimus trough drug levels of 8 to 
10 ng/ml in the first month post-transplant and 6 to 8 ng/ml thereafter.  
o AEs and SAEs will be assigned based on Common Toxicity Criteria for Adverse Events 
(CTCAE) definitions and tabulated as incidence rates per tacrolimus formulation. 
o Regular monitoring and summaries of hematology, blood chemistries, and urine results. 
o Regular monitoring of vital signs, physical condition, and body weight measurements. 
o Clinically significant infections (confirmed by culture, biopsy, genomic, radiologic, or 
serologic findings) that requires hospitalization or active anti-microbial treatment will be 
tabulated as incidence rates per tacrolimus formulation. 
o Cytomegalovirus (CMV), BK Virus, and Epstein-Barr disease will be tabulated as 
incidence rates per tacrolimus formulation. 
o dnDSA and rejection events are collected as part of standard of care in MTA-K 
o Estimated glomerular filtration rate (eGFR) will be estimated using the MRDR formula. 
 
• 
Patient-Reported Measures: Patients will complete surveys on their own unless they are unable to. 
Surveys will be administered electronically so that data will be recorded in the study’s database 
immediately and securely. The following patient reported outcomes measures will be assessed at 
both study visits.  
o HRQoL: PROMIS -29 profile (29 questions) measuring depression, anxiety, fatigue, pain 
interference, sleep disturbance, physical function, participation in social roles, and pain 
intensity 
o Symptoms: Calcineurin-inhibitor related symptoms (5 items) and the Transplant related 
symptoms (15 items) – items from PRO-CTCAE or in PRO-CTCAE format.  
o Symptoms/Tolerability: FACT- G (GP5) – Single item bothersome assessment (1 
question).  
 
• 
Adherence/Medication Satisfaction Measures: The following adherence tools/measures will be 
assessed at each study visit throughout the study for those patients capable of using an adherence 
measurement via a digital capture system: 
o The PROMIS Self-Efficacy for Managing Medication and Treatment (26 questions) – 
(study visit 1 only).  
o The Transplant Satisfaction Questionnaire for Medication – question 14.  
 

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Table of Contents 
SYNOPSIS ............................................................................................................................................ 3 
PROTOCOL ......................................................................................................................................... 9 
1. 
STUDY BACKGROUND ............................................................................................................ 9 
2. 
STUDY RATIONALE.................................................................................................................. 9 
3. 
OBJECTIVE AND ENDPOINTS ................................................................................................. 9 
4. 
PATIENT POPULATION .......................................................................................................... 11 
SCREENING FAILURE: ................................................................................................................... 12 
INCLUSION CRITERIA: .................................................................................................................. 12 
EXCLUSION CRITERIA: ................................................................................................................. 12 
5. 
STUDY DURATION.................................................................................................................. 12 
6. 
NUMBER OF PATIENTS .......................................................................................................... 12 
7. 
STUDY DESIGN ........................................................................................................................ 12 
8. 
TREATMENT ASSIGNMENT .................................................................................................. 13 
TREATMENT ARMS ..................................................... ERROR! BOOKMARK NOT DEFINED. 
9. 
STUDY METHODS AND PROCEDURES............................................................................... 13 
10. DEVIATION FROM TREATMENT ARM PROTOCOL ......................................................... 14 
CRITERIA FOR STUDY TERMINATION ...................................................................................... 14 
11. STUDY DRUG STORAGE, DISPENSING, AND ACCOUNTABILITY ................................ 14 
12. CONCOMITANT MEDICATIONS ........................................................................................... 14 
13. TREATMENT COMPLIANCE .................................................................................................. 14 
14. TIMING OF VISITS ................................................................................................................... 15 
15. SCHEDULE OF EVENTS ......................................................................................................... 16 
16. DATA COLLECTION................................................................................................................ 17 
17. CRITERIA FOR EVALUATION ............................................................................................... 17 
18. STATISTICAL ANALYSES ...................................................................................................... 18 
19. RISK/BENEFIT ASSESSMENT ................................................................................................ 18 
20. ADVERSE EVENT MANAGEMENT ...................................................................................... 19 
DEFINITION OF AN ADVERSE EVENT ........................................................................................ 19 
CLINICAL LABORATORY ASSESSMENTS AND OTHER ABNORMAL ASSESSMENTS AS 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: .................................................. 20 
RECORDING OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS............................. 20 
INTENSITY OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ............................... 20 
RELATIONSHIP OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS TO STUDY 
THERAPY .................................................................................................................................. 21 
FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ............................. 21 
TIMEFRAMES FOR SUBMITTING SAE REPORTS ..................................................................... 22 
21. PROTOCOL MODIFICATION ................................................................................................. 22 
22. REGULATORY AND ETHICAL CONSIDERATION ............................................................. 22 
23. REFERENCE .............................................................................................................................. 24 
24. INVESTIGATOR AGREEMENT .............................................................................................. 25 
25. APPENDIX 1: CALCINEURIN INHIBITOR RELATED SYMPTOM (CIRS) 
QUESTIONNAIRE..................................................................................................................... 26 
26. APPENDIX 2: TRANSPLANT RELATED SYMPTOM (CIRS) QUESTIONNAIRE ............ 27 
27. APPENDIX 3: PROMIS-29 ........................................................................................................ 30 
28. APPENDIX 4: FACT-G (GP5) & TRANSPLANT SATISFACTION QUESTIONNAIRE FOR 
MEDICATION – QUESTION 14. ............................................................................................. 33 
29. APPENDIX 5: PROMIS SELF-EFFICACY FOR MANAGING MEDICATION AND 
TREATMENT ............................................................................................................................ 34 
 
 

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PROTOCOL  
1. STUDY BACKGROUND 
 
Despite improvement in short-term graft outcomes in organ transplant, transplant patients still 
have to take on complex medication regimens to achieve current results. Adherence to these 
complex medications is an important problem in light of the potential risk of acute and chronic 
rejection and the associated burden of increased hospitalization, cost, and diminished quality of 
life that results from missed doses and poor overall drug taking. Part of the diminished quality of 
life is also tied to the bothersome symptoms patient feel after transplant. Most patients experience 
symptoms that relate to either the overall transplant immunosuppression or medication specific 
side effects. In the BENEFIT and BENEFIT-EXT trials, >60% of patients reported tiredness and 
lack of energy as an issue1. Sleep problems, mood swings, restlessness, anxiety, depression, and 
concentration and memory difficulties appeared in approximately 50-60% of patients. In addition 
to these symptoms, >38% patients also reported numerous others side effects that have been 
strongly associated with calcineurin-inhibitors such as tacrolimus that include dizziness, muscle 
cramps, trembling hands, tingling in hands and feet, and headache.  
 
2. STUDY RATIONALE  
 
We hypothesize that the use of once-daily Envarsus XR® decreases some transplant- and 
tacrolimus-related adverse symptoms and potentially leads to improvement in quality of life and 
medication adherence when compared to twice-daily tacrolimus. In order to assess this 
hypothesis, a prospective, multi-center, observational, open-label, pilot study to investigate 
medication adherence and patient reported symptom occurrence and interference with daily life 
comparing once-daily Envarsus XR® and twice-daily immediate release tacrolimus in adult renal 
transplant recipients (SIMPLE) is being proposed.  
 
The primary objective of this study is to compare tacrolimus formulations (Envarsus XR® versus 
twice a day tacrolimus) with the hypothesis that Envarsus XR® improves transplant- and 
tacrolimus- associated symptoms when compared to a twice a day tacrolimus regimen. In 
addition, as part of this study, adherence, additional patient reported outcomes (PROs), patient 
satisfaction, and health related quality of life (HRQoL) will also be measured. There is currently a 
limited amount of data available describing the side effects/symptoms that are most important 
(i.e. occur most often and are poorly tolerated) to transplant patients taking tacrolimus 
immunosuppression. These symptoms/side effects could clearly impact medication adherence. 
Furthermore, no data currently exists as to how these symptoms/side effects relate to adherence, 
quality of life, and patient satisfaction. This study will assess the correlation between adherence, 
PROs, patient satisfaction, and health related quality of life (HRQoL). It is also possible that if 
the increase in adherence is large enough; there could be a sufficient change in long-term patient 
risk for antibody mediated injury and subsequent decrease in hospitalization and cost. 
 
3. OBJECTIVE AND ENDPOINTS 
Primary Objective: The primary objective of the study is to determine if treatment with 
Envarsus XR® reduces a group of side effects that are commonly associated with calcineurin-
inhibitor therapy.  
 
Overall Hypothesis:  Treatment with Envarsus XR® leads to improved total calcineurin 
inhibitor-related symptom (CIRS) score at 1 year after kidney transplantation compared to 
immediate-release, twice-daily tacrolimus. 

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Primary Endpoint:  Difference in mean calcineurin inhibitor-related symptoms severity score at 
12 months post- kidney transplantation in Envarsus XR® group vs Control (immediate-release, 
twice-daily tacrolimus) group.   
The CIRS is a questionnaire that assesses five symptoms (from PRO-CTCAE) that have been 
shown to be associated with calcineurin inhibitors. These symptoms include trembling hands, 
muscle cramps, muscle weakness, swollen gums, and increased hair growth. Each symptom is 
based on symptom severity in the last 7 days scaled from 0 (none) – 4 (very severe). The 
cumulative score ranges from 0-20. Based on internal data, we expect a mean CIRS score in the 
control group (immediate release tacrolimus) to be around 3.8 +/- 3.6 and hypothesize a 30% 
reduction in the Envarsus XR® group. This reduction is equivalent to a 1 point difference on the 
0-20 scale or a standardized effect size (mean difference / standard deviation) of 0.29.  
 
Secondary Endpoints: 
 
1. Reduction in the population mean of any one of the five individual CIRS item including:  
trembling hands, muscle cramps, muscle weakness, swollen gums, and increased hair 
growth between the two treatment groups at 12 months 
 
2. Total percent of patients in each treatment group with a severe or very severe score (3 or 
4) on any CIRS item 12 months.  
 
3. Difference in mean transplant-related symptoms (TRS) score between treatments at 12 
months post-transplant.  
 
The TRS is a multi-item questionnaire capturing 15 symptoms (from PRO-CTCAE) that 
have been shown to be associated with transplant and general health-related quality of 
life improvement. These symptoms include change in taste, constipation, diarrhea, 
swelling in arms or legs, palpitations, dry skin, darkening of skin, blurry vision, 
headache, insomnia, anxiety, sadness, discouraged, increase in appetite, and fatigue. Each 
symptom is based on symptom severity in the last 7 days and scaled from 0 (none) – 4 
(very severe). Some symptoms also have added questions pertaining to frequency and/or 
interference with daily activities. The sum of the severity score ranges from 0-60.  The 
improvement in transplant symptoms will be measured by the difference between 
treatment groups in the mean TRS score. 
 
4. Improvement in health-related quality of life (HRQoL), as measured by the PROMIS-29 
health profile, will be compared between groups at 12 months post-kidney 
transplantation. The PROMIS-29 produces scores for depression, anxiety, fatigue, pain 
interference, sleep disturbance, physical function, participation in social roles, and pain 
intensity. Physical and mental health summary scores will also be calculated.  
 
Standardized effect sizes (mean difference / standard deviation) for differences in 
HRQOL (PROMIS-29) scores will be calculated to compare twice daily immediate 
release tacrolimus oral to Envarsus XR®.  
 
 
 

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5. Improvement in individual symptoms captured in the TRS questionnaire will be 
compared.  
The standardized effect size (mean difference / standard deviation) on TRS score will be 
calculated and compared between treatments. Individual TRS items will be classified as 
improved, worsened, unchanged and compared between treatments. 
  
6. Improvement in overall tolerability or patient bother due to side effects, measured by 
item GP5 (“I am bothered by side effects of treatment”) from the FACT-G.  
 
Patients’ GP5 responses will be classified as improved, worsened, or unchanged and 
compared between treatments. 
 
7. Improvement in mean taking adherence, defined as the percent of prescribed doses taken 
each day (as measured by electronic monitoring), rates between groups.  
The assumption is that the mean taking adherence will 75% for the twice-daily immediate 
release tacrolimus and 90% for the Envarsus XR® (and standard deviations of 38% and 
30%, respectively).  
 
8. Improved in patient medication satisfaction as assessed by Transplant Satisfaction 
Questionnaire for Medication (question 14) at 12 months post-transplant. 
Responses to the Transplant Satisfaction Questionnaire for Medication (question 14) will 
be compared between twice daily immediate release tacrolimus oral and Envarsus XR®. 
 
9. Correlation between de novo DSA (dnDSA, collected as part of standard of care in MTA-
K) and degree of taking and timing adherence.  
Proportion of patients at different adherence thresholds (>70% vs ≤70%, >80% vs ≤80%, 
>90% vs ≤90%, and 100% vs below 100%) of taking and timing adherences over 12 
months post-transplant will be correlated with the presence or absence of dnDSA by 12 
months post-transplant.   
 
10. Safety and tolerability of Envarsus XR, as measured by incidence of adverse events 
(AEs), changes in clinical safety labs, and hospitalizations.  
 
Difference between treatment groups in safety parameters including the incidence of 
adverse events (AEs), changes in clinical safety labs, and hospitalizations. 
 
4. PATIENT POPULATION 
General Consideration: 
The study population is composed of de novo solitary kidney transplant recipients who meet 
inclusion and exclusion criteria and have not been subject to investigational treatments. 
 
Enrollment Rationale: The Multicenter Transplant Alliance Kidney Consortium collectively 
transplants more than 1,500 people each year (10% of the total number of kidney transplants in 
the United States annually). Approximately 60% of these patients will be eligible for this study. 
We consider a 12 month enrollment time to be a conservative estimate. 
  
 
 

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Screening Failure: Subjects who do not meet the eligibility criteria as outlined below during 
the screening phase of the study will be considered screening failures.  
 
Inclusion criteria:  
 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
• 
Patient is an adult (18 years of age or older). 
• 
Treatment with Envarsus XR® or immediate-release, twice-daily tacrolimus has been 
indicated by patient’s transplant care team.   
• 
Patient is a recipient of a deceased or living donor kidney transplant. 
• 
Patient is able to comply with study procedures for the entire length of the study. 
• 
Patient has been informed about the study survey and has signed an informed consent form. 
 
Exclusion criteria:  
 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
• 
Patient is unable or unwilling to complete study patient reported outcome questionnaires. 
• 
Patient is currently receiving azathioprine 
• 
Patient is currently receiving an mTOR inhibitor (sirolimus, everolimus) 
• 
Patient is currently receiving an belatacept 
• 
Patient has received investigational immunosuppression 1 month prior to transplant or 
post-transplant 
• 
Patient is in a setting where a professional care taker is responsible for dispensing subject’s 
medication. 
 
5. STUDY DURATION 
 
Following enrollment, each patient will be maintained in the study for 12 months. 
 
Estimated date of first subject enrolled: May 2019 
Estimated date last subject to complete the study (12 month follow-up): May 2021 
 
6. NUMBER OF PATIENTS 
A total of 240 patients will be enrolled for the study. The enrollment will occur over a 12 month 
period.  
 
7. STUDY DESIGN  
 
Study Center(s): Multicenter Transplant Alliance – Kidney Centers   
 
Study Design:  This is a prospective, multi-center, observational, open-label, study comparing 
transplant-specific patient reported outcomes and medication adherence between Envarsus XR® 
and immediate release tacrolimus medication in adult renal transplant recipients. The study will 
enroll 240 patients and survey these same 240 patients at three time points during the study.  
 
 
 

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Study Design Rationale: 
 
Patients will be enrolled into the study within the first 30 days post-transplant. Treatment will not 
be determined by this study, and there is no intervention. The treatment decision will be made by 
each patient’s transplant care team, independent of the study.  
For the primary objective, comparison of calcineurin inhibitor related symptoms, a standard two-
group design will be used to compare treatment groups. These groups will also be compared for 
transplant-related symptoms, health-related quality of life, adverse events, patient satisfaction, 
adherence, dnDSA, and graft function. 
 
8. TREATMENT ASSIGNMENT 
This is an observational study, and as such, treatment will not be assigned, and there is no 
intervention. The treatment decision will be made by each patient’s transplant care team, 
independent of the study. 
 
9. STUDY METHODS AND PROCEDURES 
 
General: Transplant recipients will be cared for according to the site’s standard of care (SOC) 
protocols employed for post-transplant follow-up. The investigator at the site will be directly 
responsible for supervising the care of these recipients during the length of the study. 
 
Products Studied:  
 
• 
Tacrolimus (twice daily immediate release (IR) oral formulation) or  
• 
Envarsus XR® (a once daily extended-release oral tacrolimus formulation).  
Envarsus XR® is an FDA approved medication and is indicated for the prevention of organ 
rejection in de novo kidney transplant patients in combination with other immunosuppressants 
 
Medication Safety and Efficacy: Renal function, occurrence of biopsy proven acute rejection, 
development of dnDSA, and occurrence of adverse events will be assessed throughout the 
duration of the study as collected as part of standard of care or as part of study. Please see Criteria 
for Evaluation (Section 17) for detailed description of monitoring techniques.   
 
Patient-Reported Measures:  
 
• 
Patients will complete surveys on their own unless they are unable to. Surveys will be 
administered on tablets so that data will be recorded in the study’s database immediately and 
securely. The following patient reported outcome measures will be assessed at both study 
visits.  
o HRQoL: PROMIS -29 profile (29 questions) measuring depression, anxiety, fatigue, 
pain interference, sleep disturbance, physical function, participation in social roles, 
and pain intensity 
o Symptoms: Calcineurin-inhibitor related symptoms (5 items) and the Transplant 
related symptoms (15 items) – items from PRO-CTCAE or in PRO-CTCAE format.  
o Symptoms/Tolerability: FACT- G (GP5) – Single item bothersome assessment (1 
question). 
o The PROMIS Self-Efficacy for Managing Medication and Treatment (26 questions).  

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o The Transplant Satisfaction Questionnaire for Medication – question 14.  
10. DEVIATION FROM TREATMENT REGIMEN 
 
If deviation occurs from treatment, patient will continue study. Patient reported outcome 
measures will be completed as scheduled and samples will be taken as scheduled. Reason(s) for 
deviation will be recorded. 
 
Criteria for Study Termination 
The investigator can discontinue the study participant at any time for any reason, including 
development of severe adverse events, uncontrolled infection, or other clinical/administrative 
reasons. Allograft loss and death will be cause for automatic withdrawal from the study. If a 
patient unable to continue the study for any reason, an early termination visit is necessary to 
complete the study. If the patient needs be started on immunosuppression that is listed in the 
exclusion criteria of this study, an early termination visit is necessary to complete the study. 
 
11. STUDY DRUG STORAGE, DISPENSING, AND ACCOUNTABILITY 
Patient will receive open label drug through their pharmacy of choice. 
 
12. CONCOMITANT MEDICATIONS 
Subjects are required to take immunosuppressive medication to maintain allograft function. The 
patients will be on the following immunosuppression medications in addition to tacrolimus at the 
time of study entry per the inclusion criteria:  
 
• 
Mycophenolate Mofetil (CellCept®) or Mycophenolate Sodium, Enteric Coated 
(Myfortic®) (MMF) or generic equivalent formulations.  Target MMF doses will be 
between 1000 – 3000 mg/day in divided doses or the enteric coated equivalent delivered 
by mouth twice daily. The MMF dosage will be decreased or discontinued in the 
presence of adverse events as clinically warranted. Dose reduction or discontinuation will 
be documented. Adverse events that may warrant dosage modifications of MMF include 
but are not limited to gastrointestinal (gastritis, diarrhea, nausea, vomiting, dyspepsia) or 
hematological (leukopenia, thrombocytopenia, anemia or neutropenia). MMF may be 
resumed at the full dose or at a reduced dose after resolution of symptoms or the patient 
may receive an alternate adjunctive immunosuppression per the investigator’s discretion 
as long as they are not those listed in the exclusion criteria. 
 
• 
Corticosteroids. Low dose once daily oral prednisone (5-10 mg) may be administered per 
each site’s standard of practice. Doses may be increased at the discretion of the 
investigator. This most commonly occurs after pulse steroid treatment for rejection. 
 
• 
Belatacept, mTOR inhibitors, azathioprine, and investigational immunosuppression will 
not be allowed in this study. Patient who are deemed to require one of these medications 
should be removed from the study and undergo an early termination visit to complete the 
study.  
13. TREATMENT COMPLIANCE 
All subjects in the study will be adequately informed on the specific tacrolimus formulations the 
patients will receive throughout the study and the importance of compliance to the study 
protocol.  

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14. TIMING OF VISITS 
 
Visit 1: Baseline/Screening  
To be collected within the first 30 days post-transplant 
• 
Informed consent 
• 
Demographics 
• 
Medical history 
• 
Complete physical exam including vital signs, height, and weight 
• 
Determination of eligibility based on inclusion/exclusion criteria  
• 
Hematology panel 
• 
Electrolytes including creatinine and eGFR 
• 
Urinalysis  
• 
Baseline Surveys: 
o HRQoL: PROMIS -29 profile (29 questions) measuring depression, anxiety, 
fatigue, pain interference, sleep disturbance, physical function, participation in 
social roles, and pain intensity 
o PRO-CTCAE: Calcineurin-inhibitor related symptoms (5 items) and the 
Transplant related symptoms (14 items) 
o FACT – G (GP5): Single item bothersome assessment (1 question) 
o The PROMIS Self-Efficacy for Managing Medication and Treatment (26 
questions) – (study visit 1 only).  
 
Visit 2: Day 120 ± 30 days  
All subjects will complete the following prior to morning tacrolimus administration: 
• 
Vital signs, height, and weight 
• 
Hematology panel 
• 
Electrolytes including creatinine and eGFRTacrolimus trough 
• 
Surveys including: 
o HRQoL: PROMIS -29 profile (29 questions) measuring depression, anxiety, 
fatigue, pain interference, sleep disturbance, physical function, participation in 
social roles, and pain intensity 
o PRO-CTCAE: Calcineurin-inhibitor related symptoms (5 items) and the 
Transplant related symptoms (14 items) 
o FACT – G (GP5): Single item bothersome assessment (1 question) 
 
Visit 3: Day 365 ± 45 days (end of study visit) 
All subjects will complete the following prior to morning tacrolimus administration: 
• 
Vital signs, height, and weight 
• 
Hematology panel 
• 
Electrolytes including creatinine and eGFRTacrolimus trough 
• 
Surveys including: 

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o HRQoL: PROMIS -29 profile (29 questions) measuring depression, anxiety, 
fatigue, pain interference, sleep disturbance, physical function, participation in 
social roles, and pain intensity 
o PRO-CTCAE: Calcineurin-inhibitor related symptoms (5 items) and the 
Transplant related symptoms (14 items) 
o FACT – G (GP5): Single item bothersome assessment (1 question) 
o The Transplant Satisfaction Questionnaire for Medication – question 14.  
 
SCHEDULE OF EVENTS 
 
Baseline 
(Within the 
first 30 days 
post-
transplant) 
4 
 Months 
Post-
Transplant 
12 
Months 
Post-
Transplant 
(End of Study) 
 
 
 (± 30 days) 
 (± 45 days) 
STUDY VISIT NUMBER 
1 
2 
3 
Test/Procedures/Data Collection 
 
 
 
Informed Consent 
X 
 
 
Review of Inclusion/Exclusion Criteria 
X 
 
 
Demographics 
X 
 
 
Medical History 
X 
 
 
Adverse Event Assessment 
 
X 
X 
Physical exam including vital signs and weight 
X 
X 
X 
Safety labs1 
X 
X 
X 
Tacolimus trough levels 
 
X 
X 
Data collection from medical records pertaining to infection, 
immunosuppression, and graft function 
X 
X 
X 
Patient Reported Outcome Assessments 
 
 
 
PROMIS – Self-Efficacy for Managing Medications and 
Treatments v1.0 (26 items) 
X 
 
 
PROMIS-29 Profile 2.1 (29 items)  
X 
X 
X 
Calcineurin Inhibitor Related Sysmptoms (CIRS) - (5 PRO-
CTCAE items)  
X 
X 
X 
Transplant Specific(14 PRO-CTCAE items) 
X 
X 
X 
Patient Satisfaction: Treatment Satisfaction Questionnaire 
for Medication-Question 14 (1 question)  
 
 
X 
FACT-G (GP5) 
X 
X 
X 
 
 
1 
Safety Labs (CBC with differential, Electrolytes including creatinine and eGFR) 

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15. DATA COLLECTION 
 
Data will be collected at each of the MTAK sites and entered into REDCap. REDCap is a secure 
web application for building and managing online surveys and databases. REDcap is secure and 
will be managed by Mayo Clinic Rochester. REDcap is 21 CFR Part 11, FISMA, and HIPPA 
compliant and hosted on Mayo Clinic’s secure servers.  
 
Demographic information: Sex, race/ethnicity, transplant characteristics, and age will be 
collected. 
 
Medical History: Data to be collected will include medical history and medications, pathologic 
and laboratory data that are in the pre and post-transplant record. 
 
16. CRITERIA FOR EVALUATION 
 
Safety 
• 
AEs and SAEs will be assigned by Common Terminology Criteria for Adverse Events 
(CTCAE) terms and tabulated as incidence rates per tacrolimus formulation. 
• 
Hematology parameters, blood chemistries, and urine results will be monitored regularly as 
part of the participating centers’ standard of care. 
• 
Vital signs, physical condition, and body weight measurements will be monitored regularly. 
• 
Clinically significant infections (confirmed by culture, biopsy, genomic, or serologic 
findings) that requires hospitalization or active anti-microbial treatment will be tabulated as 
incidence rates per tacrolimus formulation. 
• 
Cytomegalovirus (CMV), BK Virus, and Epstein-Barr disease will be tabulated as incidence 
rates per tacrolimus formulation. 
Patient Reported Measures and Outcomes 
 
• 
Patients will complete surveys on their own unless they are unable to. Surveys will be 
administered on tablets so that data will be recorded in the study’s database immediately and 
securely. The following patient reported outcomes measures will be assessed: 
o HRQoL: PROMIS -29 profile (29 questions) measuring depression, anxiety, fatigue, 
pain interference, sleep disturbance, physical function, participation in social roles, 
and pain intensity 
o Symptoms: Calcineurin-inhibitor related symptoms (5 items) and the Transplant 
related symptoms (14 items) – items from PRO-CTCAE or in PRO-CTCAE format.  
o Symptoms/Tolerability: FACT- G (GP5) – Single item bothersome assessment (1 
question). 
 
• 
Adherence/Medication Satisfaction Measures: The following adherence tools/measures will 
be assessed at each study visit throughout the study for those patients capable of using an 
adherence measurement via a digital capture system: 
o The PROMIS Self-Efficacy for Managing Medication and Treatment (26 questions) 
– (study visit 1 only).  
o The Transplant Satisfaction Questionnaire for Medication – question 14.  

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17. STATISTICAL ANALYSES 
 
Interpretation of scores and score differences in patient-reported measures can be a difficult task 
since the scales lack the clinical meaning that is inherent in measures of survival, serum 
concentrations, or anthropometric values. To aid in interpretation of these scores, differences are 
often standardized by dividing by the standard deviation in the sample to calculate an effect size. 
There are general guidelines for small, moderate, and large effects on this standardized scale that 
can be applied to any outcome measure. A standardized effect size (mean difference / standard 
deviation) less than 0.20 is considered clinically insignificant in the field of patient-reported 
outcomes research, while effect sizes of 0.30 - 0.40 are generally considered to be minimally 
important to moderate in magnitude.  
 
For the CIRS, which had a standard deviation of 3.6 in a sample of patients receiving 
cyclosporine, an effect size of 0.30 corresponds to a difference of 1 point on the 0-20 scale. In the 
control group, we expect a mean CIRS score similar to or higher than that seen in a sample of 
patients receiving cyclosporine (3.8 +/- 3.6). A 1 point reduction in the Envarsus XR® group 
would be equivalent to a 30% reduction in calcineurin inhibitor-related symptoms. 
 
A total of 240 patients will be enrolled. Estimating 15% study dropout provides 204 patients with 
complete data at the study endpoint, which will allow us to detect effect sizes of 0.28 or larger for 
the difference between treatment arms with a 2-sided 0.05 level of significance and 80% power in 
for individual patient reported outcome measure items. This sample size is also appropriately 
powered to compare adherence rates between groups. Based on assumptions of 75% and 90% 
mean adherence, respectively, in the 2 groups (and standard deviations of 38% and 30%, 
respectively), a sample size of 110 per group will yield 90% power to obtain a significant 
difference between the 2 groups, using a 2-sample t test at a 2-sided 0.05 level of significance.  
 
For analyses of the CIRS, TRS, and PROMIS-29 scores, we will first calculate change within 
individuals from enrollment to 12 months. Analysis of covariance (ANCOVA) will be used to 
compare change between treatments, adjusted for baseline score. The ANCOVA model-estimated 
mean difference between treatments will be divided by the pooled baseline standard deviation to 
calculate effect size measures to aid in interpretation. Medication adherence and change in eGFR 
will be compared between groups using similar models. 
 
For analyses of individual transplant-related symptoms and side effect bother (GP5), within-
patient change on each item will be classified as improved, worsened or unchanged and compared 
between treatments using chi-square tests for ordinal data. Medication satisfaction responses at 12 
months will be compared between treatments using an ordinal chi-square test. 
 
18. RISK/BENEFIT ASSESSMENT 
Risk Assessment 
 
There is minimal risk or discomfort expected from participation in this research.  
 
Potential Benefits 
 
There is no direct benefit from participation in this study. Other transplant recipients may benefit 
in the future from what we learn in this study.   

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19. ADVERSE EVENT MANAGEMENT 
Definition of an Adverse Event: An Adverse Event (AE) is any untoward medical occurrence in 
a patient or clinical investigation subject temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. The occurrence does not 
necessarily have to have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.  
 
Examples of an AE include:  
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency or intensity of the condition.  
• 
Significant or unexpected worsening or exacerbation of the condition/indication under 
study.  
• 
A new condition detected or diagnosed after study therapy administration even though it 
may have been present prior to the start of the study.  
• 
Pre- or post-treatment events that occur as a result of protocol-mandated procedures (e.g., 
invasive protocol-defined procedures, modification of a patient’s previous treatment 
regimen).  
 
An AE does not include:  
• 
Medical or surgical procedures (e.g., colonoscopy, biopsy). The medical condition that 
leads to the procedure is an AE.  
• 
Social or convenience hospital admissions where an untoward medical occurrence did not 
occur.  
• 
Day to day fluctuations of pre-existing disease or conditions present or detected at the 
start of the study that do not worsen.  
• 
The disease/disorder being studied, or expected progression, signs, or symptoms of the 
disease/disorder being studied unless more severe than expected for the patient’s 
condition.  
 
Definition of a Serious Adverse Event: A Serious Adverse Event SAE) is any adverse 
experience occurring at any dose that:  
 
1. Results in death  
2. Is life-threatening (at risk of death at the time of the event)  
3. Requires in inpatient hospitalization or prolongation of existing hospitalization  
 
NOTE: Complications that occur during hospitalization are AEs. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered to be an AE.  
 
 
 

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4. Results in disability/incapacity 
NOTE: The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, accidental trauma (i.e., sprained ankle) that may interfere or prevent everyday 
life functions but do not constitute a substantial disruption. 
 
5. Is a congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in the above definition.  
 
Clinical Laboratory Assessments and Other Abnormal Assessments as Adverse Events 
and Serious Adverse Events:  
Abnormal laboratory findings (e.g. clinical chemistry, hematology, urinalysis) or other 
abnormal assessments (e.g., ECGs, vital signs) that are judged by the Investigator as 
clinically significant will be recorded as AEs or SAEs if they meet the definition of an AE 
(“Definition of an Adverse Event”) or SAE (“Definition of a Serious Adverse Event”). 
Clinically significant abnormal laboratory findings or other abnormal assessments that are 
detected during the study or are present at baseline and significantly worsen following the 
start of the study will be reported as AEs or SAEs. However, clinically significant abnormal 
laboratory findings or other abnormal assessments that are associated with the disease being 
studied, unless judged by the Investigator as more severe than expected for the patient’s 
condition, or that are present or detected at the start of the study but do not worsen, will not 
be reported as AEs or SAEs. The Investigator will exercise medical judgment in deciding 
whether abnormal laboratory values are clinically significant.  
 
Recording of Adverse Events and Serious Adverse Events  
The Investigator will review all documentation (e.g., hospital progress notes, laboratory, or 
diagnostic reports) relative to the event being reported. The Investigator will then record all 
relevant information regarding an AE/SAE into the electronic data system. It is not accept 
able for the Investigator to send photocopies of the patients’ medical records in lieu of 
completion of the appropriate AE/SAE pages. However, there may be instances when the 
medical monitor (an independent physician who is not participating in the clinical study), 
requests copies of medical records for certain cases. In this instance, all patient identifiers 
will be blinded on the copies of the medical records prior to submission to the medical 
monitor.  
 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis should be documented as the 
AE/SAE and not the individual signs and symptoms.  
 
Intensity of Adverse Events and Serious Adverse Events  
The Investigator will make an assessment of intensity for each AE and SAE reported during 
the study. The assessment will be based on the Investigator’s clinical judgment. The intensity 
of each AE and SAE will be assigned to one of the following categories:  
• 
Mild: An event that is easily tolerated by the patient, causing minimal discomfort and 
not interfering with everyday activities.  

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• 
Moderate: An event that is sufficiently discomforting to interfere with normal 
everyday activities.  
• 
Severe: An event that prevents normal everyday activities.  
 
An AE that is assessed as severe will not be confused with an SAE. Severity is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as 
severe. An event is described as ‘serious’ when it meets one of the pre-defined outcomes as 
described in “Definition of an SAE.”  
 
Relationship of Adverse Events and Serious Adverse Events to Study Therapy  
The Investigator is obligated to assess the relationship between study therapy and the 
occurrence of each AE/SAE. The Investigator will use clinical judgment to determine if there 
is a reasonable possibility that the pharmacological action of the study therapy was 
responsible for the AE/SAE being reported. Alternative causes such as natural history of the 
underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of 
the event to the study therapy will be considered and investigated. The Investigator will also 
consult the Clinical Investigator’s Brochure and/or Product Information, for marketed 
products, in the determination of his/her assessment.  
 
All AE/SAE that occur during the course of the clinical study will be evaluated and a 
determination of relatedness to the investigational product will be defined according to one of 
the following categories:  
• 
Definite - The AE/SAE is clearly related to the investigational product.  
• 
Probable - The AE/SAE is likely related to the investigational product.  
• 
Possible - The AE/SAE may be related to the investigational product.  
• 
Unlikely - The AE/SAE is doubtfully related to the investigational product.  
• 
Unrelated- The AE/SAE is clearly NOT related to the investigational product.  
There may be situations when an SAE has occurred and the Investigator has minimal 
information to include in the initial report. However, it is very important that the Investigator 
always make an assessment of causality.  
 
Follow-Up of Adverse Events and Serious Adverse Events  
After the initial AE/SAE report, the Investigator is required to proactively follow each patient 
and provide further information to the medical monitor on the patient’s condition. All AEs 
and SAEs documented at a previous visit/contact that are designated as ongoing will be 
reviewed at subsequent visits/contacts.  
 
Adverse events and SAEs will be followed until resolution, until no further changes in the 
event are expected (i.e. the point at which a patient experiencing a critical adverse event is 
treated successfully and stabilized even though they may continue to experience lingering 
sequelae that may never resolve), until the patient is lost to follow-up, or until it is agreed that 
further follow-up of the event is not warranted (e.g. non-serious, study therapy unrelated, 
mild or moderate adverse events ongoing at a patient’s final study visit). If a patient dies 
during participation in the study or during a recognized follow-up period, the medical 
monitor will be provided with a copy of any post-mortem findings, including histopathology.  
 
New or updated information will be recorded by modifying the AE forms in the electronic 
data system  
 

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Timeframes for Submitting SAE Reports  
Once an Investigator becomes aware that an SAE has occurred in a study patient, he/she will 
record the information in the electronic data record within 48 hours. Any fatal or life-
threatening event must be reported within 24 hours. If the Investigator does not have all 
information regarding an SAE, he/she will not wait to receive additional information before 
recording the event in the data system and completing as much information known at the time 
of the submission.  
 
20. PROTOCOL MODIFICATION 
 
All protocol amendments must be signed and dated by the investigator and should not be 
implemented without prior IRB approval.   
 
21. REGULATORY AND ETHICAL CONSIDERATION 
 
This study will be conducted in accordance with Good Clinical Practice (GCP) requirements 
described in the current revision of International Conference on Harmonization of Technical 
Requirements of Pharmaceuticals for Human Use (ICH) Guidelines and all applicable 
regulations. Compliance with these regulations and guidelines also constitutes compliance with 
the ethical principles described in the current revision of the Declaration of Helsinki. This study 
will also be carried out in accordance with local legal requirements. 
 
Ethics Approval  
 
It is the Investigators’ responsibility to ensure that, prior to initiating this study, this protocol is 
reviewed and approved by the appropriate local IRB. The IRB must also review and approve the 
site’s informed consent form (ICF), other written information provided to the patient, and all 
advertisements that may be used for patient recruitment. If it is necessary to amend the protocol 
or the ICF during the study, the Investigator will be responsible for ensuring that the IRB reviews 
and approves these amended documents. An IRB approval of the amended protocol and/or ICF 
must be obtained in writing before implementation of the procedures and before new patients are 
consented to participate in the study using the amended version of the ICF.  
 
Informed Consent  
 
Before being admitted to the study, all patients must consent in writing to participate. An ICF will 
be given to each patient which will contain all United States federally required elements, all ICH-
required elements, and Health Insurance Portability and Accountability Act (HIPAA) 
authorization information in language that is understandable to the patient. The process of 
obtaining the informed consent will be in compliance with all federal regulations, ICH 
requirements, and local laws. The Investigator or designee will review the study with each 
patient. The review will include the nature, scope, procedures, and possible consequences of the 
patient's participation in the study. The ICF and review will be in a form understandable to the 
patient. The Investigator or designee and the patient must both sign and date the ICF after review 
and before the patient can participate in the study. The patient will receive a copy of the signed 
and dated form, and the original will be retained in the site study files. The Investigator or his/her 
designee will emphasize to the patient that study participation is entirely voluntary and that 
consent regarding study participation may be withdrawn at any time without penalty or loss of 
health benefits to which the patient is otherwise entitled.  

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If the ICF is amended during the study, the Investigator must follow all applicable regulatory 
requirements pertaining to approval of the amended ICF by the IRB. The site must use the 
amended consent form for all new patients and, if directed by the IRB, repeat the consent process 
with the amended ICF for any ongoing patients.  
 
Confidentiality  
 
Patient’s names will remain confidential and will not be included in the database. Only patient 
number, patient initials, and birth date will be recorded in the electronic database system. If the 
patient name appears on any other document collected (e.g., hospital discharge summary), the 
name will be obliterated before the document is transmitted. All study survey documents will be 
stored in a secure location such as locked office and password protected computer. The patients 
will give explicit permission for representatives of the Sponsor, regulatory authorities, and the 
IRB to inspect their medical records to verify the information collected. Patients will be informed 
that all personal information made available for inspection will be handled in the strictest 
confidence and in accordance with all state, local, and federal data protection/privacy laws, 
including, without limitation, the HIPAA. All participants in the study will provide written 
authorization to disclose private health information either as a part of the written ICF or as a 
separate authorization form. The authorization will contain all required elements and will contain 
a waiver of patient access to study-related private health information until the conclusion of the 
clinical study. The authorization will remain valid and in full force and effect until the expiration 
of 5 years after the research program is discontinued. Individual patient medical information 
obtained during this study is confidential and its disclosure to third parties is strictly prohibited. In 
addition, medical information obtained during this study may be provided to the patient's personal 
physician or to other appropriate medical personnel when required in connection with the 
patient's continued health and welfare. The Investigator will maintain a personal patient 
identification list (patient and treatment numbers with the corresponding patient names) to enable 
records to be identified.  
 
 
 
 
 
 

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22. REFERENCE 
 
1. 
Dobbels F, Wong S, Min Y, Sam J, Kalsekar A. Beneficial effect of belatacept on health-
related quality of life and perceived side effects: results from the BENEFIT and 
BENEFIT-EXT trials. Transplantation. 2014;98(9):960-968. 
 
 
 

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23. INVESTIGATOR AGREEMENT 
 
INVESTIGATOR AGREEMENT 
I have read this protocol and agree that it contains all necessary details for carrying out this study. 
I will conduct the study as outlined herein and will complete the study within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure that 
they are fully informed regarding the conduct of the study. 
 
 
 
  
 
Investigator’s Signature* 
Date 
 
 
 
 
Name of Investigator (Typed or Printed) 
 
 
 
 
 
 
 
 
 
 
 
 
Institution, Address* 
 
 
 
 
Phone Number* 
 
 
 
 
 
 
 
 
 
Sponsor’s Responsible Signature 
Date 
 
 
 
 
Name of Medical Officer (Typed or Printed) 
 
* If the address or phone number of the investigator changes during the course of the study, 
written notification will be provided by the investigator to the sponsor and will not require 
protocol amendment(s)  
 
 
 
 

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24. APPENDIX 1: CALCINEURIN INHIBITOR RELATED SYMPTOM (CIRS) QUESTIONNAIRE  
 
 

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25. APPENDIX 2: TRANSPLANT RELATED SYMPTOM (CIRS) QUESTIONNAIRE  
 

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TRANSPLANT RELATED SYMPTOMS 
 
11. 
 
 
 
 
 
 
 
12. 
 
 
 
 
 
 
 
 
13. 
 
 
 
 
 
 
 
 
 
14. 
 
 
 
 
 
 
 
 
 
 
15. 
 
 
 
 
 
 
 
 
 

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26. APPENDIX 3: PROMIS-29 
 
 
 
 

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27. APPENDIX 4: FACT-G (GP5) & TRANSPLANT SATISFACTION QUESTIONNAIRE FOR 
MEDICATION – QUESTION 14.  
 
 
 
 
 
 
 
 
 
 

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28. APPENDIX 5: PROMIS SELF-EFFICACY FOR MANAGING MEDICATION AND TREATMENT 
 

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