A Phase 2, Prospective, Randomized, Multicenter, Open-Label, Controlled Trial to Assess the Efficacy and Safety of Exenatide SR for the Prevention of Diabetes After Kidney Transplantation.
Phase: PHASE2
Conditions: Pre Diabetes
Sponsor: Mayo Clinic

 
 
A Phase 2, Prospective, Randomized, 
Multicenter, Open-Label, Controlled Trial 
to Assess to the Efficacy and Safety of 
Exenatide SR for the prevention of 
diabetes after kidney transplantation 
 
 NCT03961256 
 
2/19/2020 

1 
 
Name of Investigational Product: Exenatide SR  
 
Title of Study:  A Phase 2, Prospective, Randomized, Multicenter, Open-Label, Controlled Trial to Assess to 
the Efficacy and Safety of Exenatide SR for the prevention of diabetes after kidney transplantation.  
Version 2.0 dated February 19, 2020 
 
Lead Investigator:   Mark D. Stegall, M.D., Mayo Clinic, Rochester, MN 
 
 
 
 
Study hypothesis  
In renal transplant recipients who have prediabetes as determined by 4 or 12 months after kidney 
transplantation, treatment with the GLP-1 receptor agonist - Exenatide SR + standard-of-care (SOC) vs. SOC 
alone will reduce the incidence of diabetes at 24 months after kidney transplantation.   
 
Intervention group 
Patients randomized to the intervention group will, in addition to standard care, receive Exenatide SR 2 mg SQ 
weekly at the time of randomization and continue until  24 months post transplant. The decision to continue 
beyond 24 months of follow-up will be left to the discretion of the caring physician. 
 
Standard care  
Participants randomized to the standard care group will receive standard post-transplant care as per Mayo 
Clinic usual practice. Standard immunosuppression includes a tacrolimus, mycophenolate with/without 
prednisone as per Mayo Clinic immunosuppression protocols.  
 
The current lifestyle standard care after kidney transplantation at Mayo Clinic hospital includes advice for 
regular exercise and a nutritional assessment. The nutrition care involves giving patients resources guiding 
them on healthy eating and food safety after transplant. 
 
 
 
Study objectives. 
 
Primary:   
To compare the rate of progression  from prediabetes from prediabetes at 4 months or 12 months  to frank 
diabetes at  24 months (as defined by increase in HbA1C or fasting BS to diabetic range based on the ADA 
criteria) after transplantation in kidney transplant recipients on Exenatide SR + SOC vs.  standard-of-care 
alone in a multicenter randomized study. 
 
Secondary:  
• 
To evaluate the rate  of progression to diabetes by 24 months after transplantation 
• 
To evaluate the safety and tolerability of Exenatide SR 
• 
To compare hemoglobin A1c levels in patients treated with Exenatide SR + SOC vs. SOC alone at  24 
months after kidney transplantation. 
• 
To compare the incidence of mesangial expansion >20% in patients treated with Exenatide SR + SOC 
vs. SOC alone at 24 months after kidney transplantation. 
• 
To compare transplant kidney function in the two arms 
• 
To compare the incidence of death by any cause in the two arms 
• 
To compare the incidence of graft loss by any cause in the two arms.  
 
Inclusion criteria:   
• 
Recipients of solitary kidney transplants (i.e. not combined liver-kidney, pancreas-kidney etc.)  
• 
Labs consistent with prediabetes, as determined at 4 and 12 months after transplantation: Prediabetes 
(fasting blood glucose 100-125 mg/dl; or 2 hr glucose 140-199 or HgbA1c 5.7-6.4%) 
 
 

2 
 
Exclusion criteria: 
• 
Diabetes pre-transplantation 
• 
Diabetes at 4 and 12 months 
• 
<18 years of age 
• 
eGFR <30 ml/min (estimated by MDRD equation from serum creatinine) 
• 
Active acute cellular rejection including borderline (If treated and resolved, these patients can be 
included) 
• 
BK nephropathy active 
• 
History of pancreatitis, pre-existing moderate-to-severe gastroparesis, liver cirrhosis or family /personal 
history of multiple endocrine neoplasia 2 or  medullary thyroid cancer 
• 
Pregnant or breastfeeding women 
Female Subject must be either: 
a. of non-child bearing potential 
1) Post-menopausal (defined as at least 1 year without any menses) prior to screening , or 
2) Documented surgically sterile or status post-hysterectomy 
b. Or if childbearing potential, 
1) Agree not to try and become pregnant during the study for at least 90 days after the final 
study drug administration. 
2) And have a negative serum or urine pregnancy test. 
3) And if heterosexually active, agree to consistently use two forms of highly effective birth 
control.  
• 
Hypersensitivity to Exenatide 
 
Criteria for Discontinuation of Medication: 
• 
Decrease in renal function to eGFR to < 30 ml/min after study initiation   
• 
Decrease in eGFR by 50% on the 2 consecutive measurements without otherwise identified cause 
which maybe correctable (like high immunosuppressive medication level, rejection, urinary tract 
infection, etc) 
• 
Intolerable GI side effects despite the optimal therapy 
• 
Thyroid tumor 
• 
Pancreatitis 
• 
Hypoglycemia 
 
Study design/schedule  
This is a Phase 2, Prospective, Randomized, Multicenter, Open-Label, Controlled Trial.  Patients are 
randomized to treatment with Exenatide SR + SOC vs. SOC alone at 4 months or 12 months post transplant 
after kidney transplantation and followed until 24 months after kidney transplantation. Patients who 
discontinued medication for AEs will be contacted within 30 days to follow up on the resolution of symptoms. 
 
Study participants with prediabetes at 4 months or 12 months after kidney transplantation will be randomized 
2:1 to receive either Exenatide SR or diet and exercise only with no medication. We plan to enroll 
approximately 50% of subjects at 4 months post transplant and 50% of subjects at 12 months post transplant 
 
Primary Endpoint is the incidence of diabetes at 24  months after kidney transplantation.   
Patients will be followed for 2 years after transplantation (20 or 12 months after enrollment) for progression to 
all endpoints.  Therefore, there will be three SOC biopsies—4, 12 and 24 months after transplantation.  
Hemoglobin A1C will be performed at the same time points. In addition 2hOGTT will be performed if clinically 
indicated per our SOC.  

5 
 
(DMGS).  77% of patients with diabetic nephropathy on 10 year biopsy did not have diabetes pre-
transplantation, and 46% were in patients without overt diabetes pre- or post-transplantation, but with 
characteristics of prediabetes including fasting hyperglycemia and obesity.  Furthermore, kidney transplants 
with DMGS had greatly inferior graft survival (Figure 1).  These data suggest that a paradigm shift is needed to 
improve the long-term graft survival for kidney transplants. 
PTDM is a pervasive problem.  In a review of UTHSA kidney transplant recipients, the incidence of PTDM was 
43% among Hispanics and 33% in non-Hispanic whites.  Patients with PTDM had a higher BMI (BMI=30.4 
kg/m2) compared with patients without PTDM (BMI=27.7 kg/m2).  Based on preliminary data from our 
collaborative analysis of the University of Michigan Transplant Center cohort, 15% of 345 kidney transplant 
recipients who did not have diabetes pre-transplant had developed PTDM based on an OGTT done at 6 
months post-transplant, and another 24% were prediabetic based on 2-hour glucose values which met the 
criteria for IGT.  Similarly, the Mayo experience (a predominantly Caucasian population) noted a 33% 
incidence of IFG at 1 year among kidney transplant recipients without diabetes pre-transplant.   
 
 
Study endpoints 
 
Primary Efficacy Endpoint:    
Incidence of diabetes at 24  months after kidney transplantation. 
Diabetes is defined based on ADA criteria for diagnosis of diabetes; 
 HbA1C>6.5%  
or FPG>126 mg/dl fasting is defined as no caloric intake for at least 8 hours)  
or 2h plasma glucose >200 mg/dl during an OGTT  
or random plasma glucose >200 mg/dl in patient with classic symptoms of hyperglycemia  
 
Based on published data, we expect that 30% of untreated patients with prediabetes at 4 months will 
develop diabetes by 12 months after transplantation. See statistical assessment section. 
 
Patients also will be followed up to 20 months after enrollment for progression to other endpoints  
 
Secondary endpoints 
• 
To evaluate the prevention of progression to diabetes by 24 months after transplantation 
• 
To evaluate the safety and tolerability of Exenatide SR 
• 
To compare hemoglobin A1c levels in patients treated with Exenatide SR + SOC vs. SOC alone at 24 
months after kidney transplantation. 
• 
To compare the incidence of mesangial expansion >20% in patients treated with Exenatide SR + SOC 
vs. SOC alone at 24 months after kidney transplantation. 
• 
To compare transplant kidney function in the two arms 
• 
To compare the incidence of death by any cause in the two arms 
• 
To compare the incidence of graft loss by any cause in the two arms.  
 
Subject Safety  
The consent process will inform a volunteer about the study, indicate that participation is voluntary and he/she 
has the right to stop at any time.  Risks will be enumerated in the informed consent form and described orally 
during the consent process.   
The potential risks to study participants include side effects of Exenatide SR (table 1) and medication 
interactions.  

6 
 
 
Table * Adverse Reactions Reported in ≥5% of Exenatide Extended ReleaseTreated 
Patients with Type 2 DM in Monotherapy Trial 
Symptom  
Percent  
Nausea 
11.3 
Diarrhea 
10.0 
Infection-site nodule 
10.5 
Constipation 
8.5 
Headache  
8.1 
Dyspepsia 
7.3 
*From the package insert  
It will also inform volunteers about the rare more severe complications including: pancreatitis, renal 
impairment, hypersensitivity, C cell thyroid tumors (the risk in humans is not determined), development of 
antibodies to the medication, hypoglycemia when use with other medications for diabetes (oral or insulin) 
DRUG INTERACTIONS  
• May impact absorption of orally administered medications.  
• Warfarin: Postmarketing reports with exenatide of increased INR sometimes associated with bleeding. 
Monitor INR frequently until stable upon initiation of BYDUREON therapy 
Patients will be monitored for any drug interactions with immunosuppression and other medications. 
Immunosuppression levels will be monitored as outlined below. Recipients on Warfarin will be ask to monitor 
their INR through the local Anticoagulation Clinics or PCP as per patient’s preference frequently and per local 
protocols until INR levels are stable.   
Stopping Rules. 
In general, the study drug is well-tolerated and we expect the same in kidney transplant recipients. 
Enrollment will be suspended for any of the following: 
• 
2 hospital admissions that are deemed related to study drug 
• 
A patient death in the study arm.  This will be investigated for possible causal relation to study drug. 
 
In addition, the investigator also has the right to withdraw patients from the study for any of the following 
reasons: 
• 
Concurrent illness 
• 
Occurrence of an unacceptable adverse event (see Individual stopping criteria, above). 
• 
Patient request 
• 
Protocol violations 
• 
Non-compliance 
• 
Administrative reasons 
• 
Failure to return for follow-up 

7 
 
• 
General or specific changes in the patient’s condition unacceptable for further treatment in the 
judgment of the investigator 
 
At the time of withdrawal, all study procedures outlined for the End of Study visit should be completed.  The 
primary reason for a patient’s withdrawal from the study is to be recorded in the source documents. 
Patients who discontinue treatment will be followed for 30 days to capture possible delayed onset AEs.  
 
 
Safety reporting plan  
Safety will be assessed using incidence of all adverse events (AEs), serious adverse events (SAEs), 
treatment-emergent adverse events (TEAEs) and AEs leading to study withdrawal; review of laboratory data, 
including hematology, renal function, biochemistry; new concomitant medication usage; hospitalization rates; 
and vital signs.  Adverse events will be classified for serious adverse events using standard regulatory criteria.   
Other safety endpoints include the incidence of BK nephropathy, opportunistic infections, and malignancies.  
 
Data Confidentiality  
A participant’s privacy and confidentiality will be respected throughout the study.  Each participant will be 
assigned a unique identification number and these numbers rather than names will be used to collect, store, 
and report participant information.  Site personnel will not transmit documents containing personal health 
identifiers (PHI) to the study sponsor or their representatives.  
 
Study Documentation 
 All clinical data is maintained in Microsoft Excel. All study data is downloaded from this database and stored in 
tables within a separate Microsoft Access file.  Study data is output into study files (xls, jmp, doc, ppt, etc.), 
which are used for summarizing study information.  All active study files are stored within a folder on the 
Transplant Center research server.  The investigator is required to ensure that all clinical data is complete for 
all participants   
 
Study Coordination  
Study coordinators will assist in monitoring participant safety, evaluating the progress of the study, and 
reviewing procedures for maintaining the confidentiality of data and the quality of data collection, management, 
and analyses.  
 
 
Preliminary data: 
We identified 17 kidney transplant recipients who were started on GLP-1 agonists for diabetes  in our 
institution. Discontinuation rate was 17% (similar to non transplant population). Medication was effective in 
reducing weight, controlling diabetes and decreasing the insulin requirements. Abstract submitted to American 
Transplant Congress (attached).     
 
Collecting, monitoring and reporting of serious adverse events.  
Adverse events will be recorded by PI/co-PI or the care team member in patient medical record using a 
recognized medical term or diagnosis that accurately reflects the event. Patients will be encouraged to contact 
care team members by the phone or electronically and reported events will be reviewed by PI/co-PI. Patients 
will have labs monitored and visits scheduled per standard of care as outlined in the protocol. Additionally, 
PI/co-PI or designated person on research team will follow up with patient by the phone call or electronically at 
7-14 days and 90± 7 days after initiation of drug with open ended questions. Adverse events will be considered 
based on patient reported symptoms, examinations and laboratory data.  Adverse events will be assessed by 
the investigator for severity, relationship to the investigational product, possible etiologies, and whether the 
event meets criteria of an SAE and therefore requires immediate notification to AstraZeneca Patient Safety.  

8 
 
Study recording period and follow-up for adverse events and serious adverse events 
Adverse events and serious adverse events will be recorded from time of signature of informed consent, 
throughout the treatment period and including the follow-up period.  
All SAEs will be reported, whether or not considered causally related to the investigational product, or to the 
study procedure(s). The reporting period for SAEs is the period immediately following the time that written 
informed consent is obtained through 90 days after the last dose of investigational product. The investigators 
are responsible for informing the Ethics Committee and/or the Regulatory Authority of the SAE as per local 
requirements. 
The investigator will  inform the FDA, via a MedWatch form, of any serious or unexpected adverse events that 
occur in accordance with the reporting obligations of 21 CFR 312.32 , and will concurrently forward all such 
reports to AstraZeneca. A copy of the MedWatch report will be emailed to AstraZeneca (TCS vendor) at the 
time the event is reported to the FDA. 
Sponsor must also indicate, either in the SAE report or the cover page, the causality of events in relation to all 
study medications and if the SAE is related to disease progression, as determined by the principal investigator. 
PI or co-PI will send SAE report and accompanying cover page by way of email to AstraZeneca’s 
designated mailbox: 
 
If a non-serious AE becomes serious, this and other relevant follow-up information will be provided to 
AstraZeneca and the FDA. 
Serious adverse events that do not require expedited reporting to the FDA still need to be reported to 
AstraZeneca preferably using the MedDRA coding language for serious adverse events.  
Safety/Tolerability Outcomes Measures: 
 
 
1. Percentage of Participants with at Least 1 Grade ≥2 Treatment Emergent Adverse Event (TEAE) 
According to Common Terminology Criteria for Adverse Events (CTCAE)  
A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that 
occurs after receiving study drug (AE start date greater than or equal to [≥] first dose date) and 
within 30 days after receiving the last dose of study drug (AE start date - last dose date less than 
or equal to [≤] 30). A TEAE may also be a pre-treatment adverse event or a concurrent medical 
condition diagnosed prior to the date of first dose of study drug, which increases in intensity after 
the start of dosing. 
 
2. Percentage of Participants with at Least 1 Serious Adverse Event (SAE)  
A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose 
results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing 
hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / 
birth defect or is medically important due to other reasons than the above mentioned criteria. 
 
3. Percentage of Participants with at Least 1 Adverse Event Leading to Discontinuation of 
Investigational Study Medication  
Withdrawal due to an AE will occur if the participant experiences an AE that requires early 
termination because continued participation imposes an unacceptable risk to the participant's 
health or the participant is unwilling to continue because of the AE. 

9 
 
 
 
 
Safety reporting plan  
Safety will be assessed using incidence of all adverse events (AEs), serious adverse events (SAEs), 
treatment-emergent adverse events (TEAEs) and AEs leading to study withdrawal; review of laboratory data, 
including hematology, renal function, biochemistry and microbiology and malignancies; new concomitant 
medication usage; hospitalization rates; and vital signs.  Adverse events will be classified for serious adverse 
events using standard regulatory criteria. 
 
Statistical analysis plan. 
Study design and analysis will be performed according to intention to treat principles.  Time to development of 
PTDM will be compared utilizing Kaplan-Meier curves generated according to the product limit method utilizing 
log-rank tests to evaluate intergroup differences.  Risk adjustment for baseline differences between groups will 
be assessed according to multivariate proportional hazards models.  Data on patients who withdraw or are lost 
to follow-up will be censored at the time of last visit.  Comparisons of repeated measures between groups 
including the secondary endpoints outlined above will be performed utilizing general linear mixed models with 
transformation of data to logarithm forms when appropriate.  These comparisons will be made with inclusion of 
subjects who withdraw within the follow-up period. Sensitivity analysis excluding these patients will also be 
performed. 
Needed sample size was calculated according to development of PTDM based on utilization of a 2-sided chi-
squared test at a 5% significance level and 80% power. The incidence of PTDM reported after kidney 
transplant varies from 2-50% with best estimates indicating that approximately 30% of patients will develop 
PTDM.3,4,41,42 The SCALE trial comparing GLP-1 receptor agonists to placebo showed an 80% reduction in 
development of type 2 diabetes.21 Other clinical trials evaluating prevention of diabetes showed a 30% risk 
reduction with metformin and 55-72% reduction with TZDs.29,43 Thus, sample size was calculated based on a 
proportion of 30% incidence of PTDM in the control group and 80% risk reduction in the experimental group 
(consistent with SCALE trial). A total of 81 (54:27 according to 2:1 randomization) patients will be required to 
achieve the power and significance levels above.  In our preliminary data, 24-33% of kidney transplant 
recipients meet prediabetes criteria.  We would expect that full enrollment would take 24 months.   
 
Data management plan 
The coordinating center will be the primary contact for this study and the data coordinating center:  
Dr. Mark D. Stegall and his program coordinator, M
 L
 (
 and 
stegall.mark@mayo.edu) 
1. 
The FDA investigator-initiated IND will be held by Dr. Stegall 
2. 
Contracts will preferentially be through the Coordinating Center with subcontracts to the other sites.  
Indirect costs will be charged only once (i.e. at the site where the funds are actually spent). 
3. 
Protocols will be approved by local IRB (the three Mayo sites have a central IRB). 
4. 
Data is entered into a common database with case-report forms similar to any FDA 
studies(MEDIDATA Rave case forms specific for transplant are already in place) 
5. 
The Coordinating Center will be responsible for data cleanup, data reporting and reporting to the 
sponsors and the FDA. 
6. 
Histology:   
                 Mesangial expansion by light microscopy  
 
 
 

10 
 
Schedule of visits 
 
Enrollment Day 122 (4 months)  
 
Enrollment 
Day 122  
after KTx 
range 90-
180 days 
Day 7±3 
 Days 
Post 
enrollment  
Monthly 
labs to 1 
year 
per SOC 
 
Day 
90±7 
Day 365 
±90  
after KTx 
 
Labs 
q3 months 
from 12-24 
months 
 
Day 730 ± 90 
after KTx 
Consent 
x 
 
 
 
 
 
 
Labs 
x 
x 
x 
 
x 
x 
x 
Clinic visit 
x 
 
 
 
x 
 
x 
Communicatio
n through 
phone call or 
EMR 
 
x 
 
 
x 
 
x 
 
HgbA1c 
 
 
 
 
x 
x 
x 
Biopsy 
x 
 
 
 
x 
 
x 
Pregnancy test 
x 
 
 
 
 
 
 
 
 
Enrollment Day 365 (1 year)  
 
Enrollment 
Day  365  
after KTx 
range 300-
420 days 
Day 7±3 
 Days 
Post 
enrollment  
Labs q 3 
months  
per SOC 
 
Day 
90±7 
 
Day 730 ± 90 
after KTx 
Consent 
x 
 
 
 
 
Labs 
x 
x 
x 
 
x 
Clinic visit 
x 
 
 
 
x 
Communication 
through phone 
call or EMR 
 
x 
 
 
x 
 
HgbA1c 
 
 
 
 
x 
Biopsy 
x 
 
 
 
x 
Pregnancy test 
x 
 
 
 
 
 
All labs are standard of care, except for the pregnancy test. Day 7 labs represent current practice of repeating 
labwork  with any significant changes in medical therapy. Day 7 labs will include CBC, basic metabolic panel 
(BMP), which includes creatinine, BUN and electrolytes and immunosuppression levels, including Tacrolimus 
level and MPA (CellCept). CBC, BMP and Tacrolimus levels will be performed monthly thereafter up to 12 
months post transplant and q3 months indefinitely. All labs obtained are standard clinical labs per local practice 
and monitored by the licensed clinical nurses or physicians following the patient’s clinical care.   Additional labs 
will be done as dictated per current standard of care. If there is a lab value out of reference, study staff would 
also bring it to the clinical staff’s attention, but research staff would not dictate or change the clinical care of the 
patient unless it was directly related to study drug and were directed by the PI/Co-PI 
 
Publication plan.  Results will be written up for publication and submitted to a transplant journal such as the 
American Journal of Transplantation or Transplantation.  Similar to prior studies, we also will submit this data 
as an abstract/oral presentation to the American Transplant Congress annual meeting. 
 
POTENTIAL CHALLENGES: Performing this initial trial within the Mayo sites represents crucial evidence 
needed to determining the efficacy as well as safety and tolerability of GLP-1 receptor agonists in the 

11 
 
transplant population.  Other trials are required to investigate the efficacy of these anti-diabetic medications in 
other solid organ transplant recipients such as liver transplant patients who also experience a high incidence of 
PTDM.   
Determining significance in longitudinal changes in allograft protocol biopsies related to diabetic nephropathy in 
prediabetic patients is beyond the scope of this trial.  However, this data based on samples collected per 
standing clinical protocols will provide innovative and generalizable knowledge related to the renal changes in 
prediabetics that has otherwise not been available.  The preliminary data obtainable through the exploration of 
this specific aim will be of great value in broadening the scientific knowledge related to the relationship 
between prediabetes and diabetic nephropathy and determining key endpoints for designing future diabetes 
prevention trials in solid organ transplant recipients. 
FUTURE DIRECTIONS: Given the pervasiveness of diabetes and prediabetes in kidney and other solid organ 
transplant recipients, well-designed clinical trials aimed at determining best therapy for preventing and 
improving treatment of diabetes after transplantation are desperately needed.  The concomitant use of 
diabetogenic agents, including corticosteroids and calcineurin inhibitors, and the common weight gain 
experienced after transplant create a challenging environment to deal with these problems, but also 
emphasizes the importance of addressing these concerns.  The completion of a prospective, feasibility trial will 
help obtain needed data about the safety, tolerability, and efficacy of GLP-1 receptor agonists in kidney 
transplant recipients and specifically Hispanic patients. Improved treatment of prediabetes and diabetes after 
kidney transplantation may portend the realization of goals to enhance long-term kidney graft outcomes, as 
well as improve the health and survival of these patients. 
 
Specific Methods. 
Prediabetes and diabetes are determined using standard serum blood glucose level determinations including:  
fasting serum glucose, 2 hour post serum glucose in an OGTT and HbA1c. 
eGFR is based on serum creatinine levels using MDRD48 
 
Light Microscopy 
Light microscopy will be used to determine the percentage of (1) global glomerulosclerosis (GGS) involving 
>20% of the glomeruli (GGS; 0 = 0%, 1 = ≤20%, 2 = >20%); and (2) mesangial matrix expansion (or mesangial 
sclerosis, MS) as defined as mild (1), moderate (2) and severe (3) averaged over all of the glomeruli in each 
biopsy sample 
 
 
                                                                                                                                                  
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3. 
Woodward RS, Schnitzler MA, Baty J, et al. Incidence and cost of new onset diabetes mellitus among 
U.S. wait-listed and transplanted renal allograft recipients. Am J Transplant. 2003;3(5):590-598. 
4. 
Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ. Diabetes mellitus after kidney transplantation in the 
United States. Am J Transplant. 2003;3(2):178-185. 

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