Conditions: Type2 Diabetes Kidney Diseases
Keywords: albuminuria GLP-1 Receptor Agonist Type 2 Diabetes
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 15
Healthy volunteers: no

Brief summary:
This is a prospective study to evaluate effect of Exenatide extended release treatment for 1 year on albuminuria levels in T2DM patients with micro- and macroalbuminuria compared to placebo.

Detailed description:
This is a prospective study to evaluate effect of Exenatide extended release treatment for 1 year on albuminuria levels in T2DM patients with micro- and macroalbuminuria compared to placebo. The similarities in baseline values between the study groups will be compared using appropriate parametric tests. Transformations of the data on order to meet statistical assumptions may be considered. All statistical analysis will be carried out using SPSS software (SPSS Inc, Chicago, Illinois) based on intention to treat principle. Data will be presented as mean±standard error. The primary endpoint of the study is the change from baseline in albuminuria level at weeks 12, 26, 39 and 56 following Exenatide extended release and placebo treatments. Fasting samples collected at weeks 0, 12, 26, 39 and 56 will be used for this assessment with values at week 0 considered as baseline. Changes from baselines form both drugs arms will be compared to those from the placebo arms in both the micro and macroalbuminuria groups. The statistical analysis will be done using mixed model for repeated measurement (MMRM) analysis with assigned α value of 0.05. Our preliminary data on retrospective analysis of the difference in albuminuria following GLP-1RA treatment for 2.5 yrs in T2DM patients with micro and macroalbuminuria show regression of albuminuria (UACR) by approximately 55mg/mg and 500mg/g (about 50% reduction), respectively. Conservatively estimating a difference in the change from baseline in albuminuria after 1 year between the Exenatide extended release and placebo groups (across both albuminuria groups) of 60mg/g, with standard deviation of no more than 91mg/g, a sample size of 38 patients per group should provide adequate power (beta = 0.2) to detect a significant difference (alpha = 0.05). Assuming a drop-out rate of 15% and 2:1 drug:placebo randomization ratio, 60 active and 30 control will be recruited for a total of 90 patients (rounded up). Patients will be enrolled based on a predetermined stratification according to the two albuminuria categories (micro and macro at 1:1 ratio) with 45 patients in each.

The secondary end points include the comparison of the changes in albuminuria based on baseline albuminuria category (micro or macro), creatinine clearance, Cystatin C, TGFβ, type I and IV collagen, CTGF, and fibronectin levels, the expression of SMAD3, SMAD4, NQO-1, GST-1P and HO-1, Nrf-2/keap-1 system activation between the Exenatide extended release and placebo groups and across albuminuria categories

Arms:
arm 1: Exenatide extended release treatment for 1 year on albuminuria levels in T2DM patients with micro- and macroalbuminuria compared to placebo. arm 2: Placebo treatment for 1 year on albuminuria levels in T2DM patients with micro- and macroalbuminuria compared to Exenatide extended release.

Interventions: intervention 1: Exenatide Extended Release for Inj Susp 2 MG intervention 2: Placebo
Intervention descriptions: intervention 1: Exenatide extended release treatment weekly for 1 year in T2DM patients with micro- and macroalbuminuria intervention 2: placebo treatment weekly for 1 year in type 2 diabetes with micro-and macroalbuminuria

Protocol document:
Prot_SAP_002.pdf: 
 
University at Buffalo Institutional Review Board (UBIRB) 
Office of Research Compliance | Clinical and Translational Research Center Room 5018 
875 Ellicott St. | Buffalo, NY 14203 
UB Federalwide Assurance ID#: FWA00008824 
Page 1 of 42 
 
 
PROTOCOL TITLE: 
Include the full protocol title. 
Response:  GLP-1 Receptor Agonist Therapy and Albuminuria in 
Patients with Type 2 Diabetes  
 
PRINCIPAL INVESTIGATOR: 
Response:  
Principal Investigator:  
Paresh Dandona, MBBS, PhD 
Co- Investigators: 
 
Husam Ghanim, PhD 
 
 
 
 
Manav Batra, MD 
 
 
 
Paresh Dandona, M.B.B.S., Ph.D., F.R.C.P, F.A.C.P, F.A.C.C, FACE, 
SUNY Distinguished Professor, 
Director, Diabetes-Endocrinology Center of Western NY 
Chief of Endocrinology, Diabetes, Endocrinology and Metabolism, SUNY at Buffalo 
1000 Youngs Rd, Suite 105,  
Williamsville, NY 14221 
Telephone: (716) 535-1850 
Fax: 716 639-1200 
E-mail: pdandona@kaleidahealth.org 
 
VERSION: 
Include the version date or number. 
Response: 10/12/2018, V3 
 
 
 


 
Page 2 of 42 
IRB Version: JAN2016 
 
Complete Research Protocol (HRP-503) 
 
Table of Contents 
Template Instructions.......................................................................................................... 3 
1.0 
Objectives ................................................................................................................ 5 
2.0 
Scientific Endpoints ................................................................................................. 6 
3.0 
Background .............................................................................................................. 7 
4.0 
Study Design .......................................................................................................... 12 
5.0 
Local Number of Subjects ..................................................................................... 13 
6.0 
Inclusion and Exclusion Criteria ............................................................................ 13 
7.0 
Vulnerable Populations .......................................................................................... 15 
8.0 
Eligibility Screening .............................................................................................. 16 
9.0 
Recruitment Methods ............................................................................................. 17 
10.0 Procedures Involved............................................................................................... 18 
11.0 Study Timelines ..................................................................................................... 21 
12.0 Setting .................................................................................................................... 22 
13.0 Community-Based Participatory Research ............................................................ 22 
14.0 Resources and Qualifications ................................................................................. 23 
15.0 Other Approvals ..................................................................................................... 24 
16.0 Provisions to Protect the Privacy Interests of Subjects .......................................... 24 
17.0 Data Management and Analysis ............................................................................ 25 
18.0 Confidentiality ....................................................................................................... 26 
A. 
Confidentiality of Study Data ............................................................................ 26 
B. 
Confidentiality of Study Specimens ................................................................... 27 
19.0 Provisions to Monitor the Data to Ensure the Safety of Subjects .......................... 28 
20.0 Withdrawal of Subjects .......................................................................................... 30 
21.0 Risks to Subjects .................................................................................................... 31 
22.0 Potential Benefits to Subjects ................................................................................ 32 
23.0 Compensation for Research-Related Injury ........................................................... 32 
24.0 Economic Burden to Subjects ................................................................................ 33 
25.0 Compensation for Participation ............................................................................. 33 
26.0 Consent Process ..................................................................................................... 34 
27.0 Waiver or Alteration of Consent Process ............................................................... 38 
28.0 Process to Document Consent ............................................................................... 38 
29.0 Multi-Site Research (Multisite/Multicenter Only)................................................. 39 
30.0 Banking Data or Specimens for Future Use .......................................................... 39 
31.0 Drugs or Devices.................................................................................................... 40 
32.0 Humanitarian Use Devices .................................................................................... 42 
 
 
 


 
Page 3 of 42 
IRB Version: JAN2016 
Template Instructions 
Sections that do not apply: 
• In several sections, the addition of checkboxes for Not Applicable have been 
added to the template as responses.   
o If an N/A checkbox is present, select the appropriate justification 
from the list.   
o If an N/A checkbox is not present, or if none of the existing 
checkboxes apply to your study, you must write in your own 
justification. 
• In addition: 
o For research where the only study procedures are records/chart 
review:  Sections 19, 20, 22, 23, 24, 25, 31, and 32 do not apply. 
o For exempt research:  Sections 31 and 32 do not apply. 
 
Studies with multiple participant groups: 
 
• If this study involves multiple participant groups (e.g. parents and children), 
provide information in applicable sections for each participant group. Clearly 
label responses when they differ.  For example: 
Response:  
Intervention Group:  
 
Control Group: 
 
Formatting: 
• Do not remove template instructions or section headings when they do not apply 
to your study. 
If you are pasting information from other documents using the “Merge Formatting” 
Paste option will maintain the formatting of the response boxes. 
Amendments: 
• When making modifications or revisions to this and other documents, use the 
Track Changes function in Microsoft Word. 
• Update the version date or number on Page 3. 
 
 


 
Page 4 of 42 
IRB Version: JAN2016 
PROTOCOL TITLE: 
Include the full protocol title. 
Response:  GLP-1 Receptor Agonist Therapy and Albuminuria in 
Patients with Type 2 Diabetes  
 
PRINCIPAL INVESTIGATOR: 
Response:  
Principal Investigator:  
Paresh Dandona, MBBS, PhD 
Co- Investigators: 
 
Husam Ghanim, PhD 
 
 
 
 
Manav Batra, MD 
 
 
 
Paresh Dandona, M.B.B.S., Ph.D., F.R.C.P, F.A.C.P, F.A.C.C, FACE, 
SUNY Distinguished Professor, 
Director, Diabetes-Endocrinology Center of Western NY 
Chief of Endocrinology, Diabetes, Endocrinology and Metabolism, SUNY at Buffalo 
1000 Youngs Rd, Suite 105,  
Williamsville, NY 14221 
Telephone: (716) 535-1850 
Fax: 716 639-1200 
E-mail: pdandona@kaleidahealth.org 
 
VERSION: 
Include the version date or number. 
Response: 10/12/2018, V3 
 
 
GRANT APPLICABILITY: 
Indicate whether this protocol is funded by a grant (e.g. NIH, foundation grant).  
For a grant with multiple aims, indicate which aims are covered by this research 
proposal. 
NOTE: This question does not apply to studies funded by a sponsor contract. 
Include a copy of the grant proposal with your submission.     
Response: Astra Zeneca  
 


 
Page 5 of 42 
IRB Version: JAN2016 
RESEARCH REPOSITORY: 
Indicate where the research files will be kept, including when the study has been 
closed.  The repository should include, at minimum, copies of IRB 
correspondence (approval, determination letters) as well as signed consent 
documents.  This documentation should be maintained for 3 years after the study 
has been closed.   
Response: Diabetes Endocrinology Research Center of WNY 
Location/ Address: 1000 Youngs Rd, Suite 105, Williamsville, NY 14221 
Department: Diabetes Endocrinology  
 
1.0 
Objectives 
1.1 Describe the purpose, specific aims, or objectives of this research. 
Response:   
Aim 1.1: To compare changes in albuminuria levels (UACR) following 1-year treatment 
with exenatide-extended release (weekly exenatide) or placebo in T2DM with macro- and 
microalbuminuria. 
Aim 1.2: To evaluate changes in creatinine, creatinine clearance, GFR and cystatin C 
following 1-year treatment with exenatide-extended release (weekly exenatide) or placebo 
in T2DM with macro- and microalbuminuria. 
  
Aim 2.1: To evaluate the changes in TGFβ levels and in the expression of two major signal 
transducers of TGF signaling, SMAD3 and SMAD4 in MNC following 1-year treatment 
with exenatide-extended release or placebo in T2DM with macro- and microalbuminuria. 
Aim 2.2: To investigate the changes in profibrotic genes such as type I and IV collagen, 
connective tissue growth factor (CTGF), PAI-1, TIMP-1 and 2 and fibronectin (fibronectin 
EDA) following 1-year treatment with exenatide-extended release or placebo in T2DM 
with macro- and microalbuminuria. 
  
Aim 3.1: To evaluate the change in reactive oxygen species (ROS) generation and NADPH 
oxidase subunit (p47phox) in MNC and urinary isoprostanes following 1-year treatment with 
exenatide-extended release or placebo in T2DM with macro- and microalbuminuria. 
Aim 3.2: To investigate the changes in Nrf-2/keap-1 system activation and anti-oxidant 
response genes including NQO-1, GST-1P and HO-1 expression following 1-year 
treatment with exenatide-extended release or placebo in T2DM with macro- and 
microalbuminuria 
1.2 
State the hypotheses to be tested, if applicable. 
NOTE:  A hypothesis is a specific, testable prediction about what you expect to 
happen in your study that corresponds with your above listed objectives. 
Response: Hypothesis 1: Treatment with weekly exenatide reduces the rate of progression 
and possibly reverses the rate of albuminuria in patients with type 2 diabetes (T2DM).  
Hypothesis 2 (exploratory): Exenatide extended release treatment suppresses TGF-β1 
activation in T2DM with micro and macroalbuminuria.  
 


 
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IRB Version: JAN2016 
Hypothesis 3 (exploratory): Exenatide extended release treatment suppresses oxidative 
stress and induces anti-oxidant mediators in T2DM with micro and macroalbuminuria.  
 
 
2.0 
Scientific Endpoints 
 
2.1    Describe the scientific endpoint(s), the main result or occurrence under 
study.   
 
NOTE:  Scientific endpoints are outcomes defined before the study begins to determine 
whether the objectives of the study have been met and to draw conclusions from the data.  
Include primary and secondary endpoints.  Some example endpoints are:  reduction of 
symptoms, improvement in quality of life, or survival.  Your response should not be a 
date.   
Response:  
 This is a prospective study to evaluate effect of Exenatide extended release treatment for 
1 year  on albuminuria levels in T2DM patients with micro- and macroalbuminuria 
compared to placebo. The similarities in baseline values between the study groups will be 
compared using appropriate parametric tests. Transformations of the data on order to meet 
statistical assumptions may be considered. All statistical analysis will be carried out using 
SPSS software (SPSS Inc, Chicago, Illinois) based on intention to treat principle. Data 
will be presented as mean±standard error. The primary endpoint of the study is the change 
from baseline in albuminuria level at weeks 12, 26, 39 and 56 following Exenatide 
extended release and placebo treatments. Fasting samples collected at weeks 0, 12, 26, 39 
and 56 will be used for this assessment with values at week 0 considered as baseline. 
Changes from baselines form both drugs arms will be compared to those from the placebo 
arms in both the micro and macroalbuminuria groups. The statistical analysis will be done 
using mixed model for repeated measurement (MMRM) analysis with assigned α value 
of 0.05. Our preliminary data on retrospective analysis of the difference in albuminuria 
following GLP-1RA treatment for 2.5 yrs in T2DM patients with micro and 
macroalbuminuria show regression of albuminuria (UACR) by approximately 55mg/mg 
and 500mg/g (about 50% reduction), respectively. Conservatively estimating a difference 
in the change from baseline in albuminuria after 1 year between the Exenatide extended 
release and placebo groups (across both albuminuria groups) of 60mg/g, with standard 
deviation of no more than 91mg/g, a sample size of 38 patients per group should provide 
adequate power ( = 0.2) to detect a significant difference ( = 0.05). Aassuming a drop-
out rate of 15% and 2:1 drug:placebo randomization ratio, 60 active and 30 control will 
be recruited for a total of 90 patients (rounded up). Patients will be enrolled based on a 
predetermined stratification according to the two albuminuria categories (micro and 
macro at 1:1 ratio) with 45 patients in each. 
The secondary end points include the comparison of the changes in albuminuria based on 
baseline albuminuria category (micro or macro), creatinine clearance, Cystatin C, TGFβ, 
type I and IV collagen, CTGF, and fibronectin levels, the expression of SMAD3, SMAD4, 
NQO-1, GST-1P and HO-1, Nrf-2/keap-1 system activation between the Exenatide 
extended release and placebo groups and across albuminuria categories.  


 
Page 7 of 42 
IRB Version: JAN2016 
 
3.0 
Background 
3.1 Provide the scientific or scholarly background, rationale, and significance of 
the research based on the existing literature and how it will contribute to 
existing knowledge.  Describe any gaps in current knowledge.  Include relevant 
preliminary findings or prior research by the investigator.  
Response:  
Diabetic nephropathy is the leading cause of chronic kidney disease accounting for nearly 
50% of all end-stage renal disease worldwide (1). Current therapies that aim to lower blood 
glucose are not effective in blocking renal damage, and cotreatment with renoprotective 
drugs often results in toxicity, limiting efficacy. Hence, there remains an urgent need to 
develop effective medicines to preserve normal renal function and to prevent or slow the 
progression of diabetic nephropathy.  
 
Although diabetic nephropathy involves many renal cell types, mesangial activation by 
cytokines under hyperglycemic conditions plays an important role in the progression of 
diabetic nephropathy (2). The cytokine transforming growth factor-β1 (TGF-β1) is central 
to the profibrotic switch and activation of mesangial cell hypertrophy and matrix 
production and is upregulated in diabetic nephropathy (3). Previous interventions at the 
level of TGF-β1 ameliorated several pathological symptoms of diabetic nephropathy (4), 
indicating reduction of hypertrophy and extracellular matrix (ECM) accumulation in the 
kidney may be a viable therapeutic avenue.  
 
The transcription factor NFE2-related factor 2 (Nrf2) is an emerging therapeutic target for 
several diseases Nrf2 regulates expression of numerous genes through antioxidant response 
elements in their promoters to neutralize free radicals and accelerate removal of 
environmental toxins (5). Using streptozotocin (STZ)-induced diabetic models, a 
protective role of Nrf2 against renal damage through mediation of free radicals was 
demonstrated (6). This may be also associated with the suppression of TGFβ related genes 
including fibronectin, collagen IV and thrombospondin-1 (TSP-1), which too are known to 
contribute to the pathogenesis of diabetic nephropathy. In addition, recent work has shown 
that heparanase, the enzyme which destroys heparan sulfate, an important integral part of 
the glomerular basement membrane, may also contribute to the pathogenesis of diabetic 
nephropathy (7).  
 
Treatment of type 2 diabetes with GLP-1 receptor agonists over the past decade has 
revealed a number of important attributes of this drug class besides their ability to improve 
glycemic control through increased insulinogenesis, decreased glucagon secretion, slowing 
of gastric emptying and the suppression of appetite and carbohydrate intake (8-10). We 
reported for the first time that exenatide, the first marketed drug in this class, induced a 
significant reduction in systolic blood pressure and plasma CRP concentrations. The latter 
observation was indicative of an anti-inflammatory effect. The systolic blood pressure 
lowering effect of exenatide, liraglutide and other drugs in this class has now been 
confirmed by other studies, including our own, in both type 2 and type 1 diabetes. In 
addition, the reduction in CRP concentrations has been followed by studies demonstrating 


 
Page 8 of 42 
IRB Version: JAN2016 
a rapid and comprehensive ROS suppressive and anti-inflammatory action of exenatide at 
the cellular and molecular level. Since hypertension and oxidative and inflammatory stress 
are major factors in the pathogenesis of diabetic nephropathy, we wondered whether 
exenatide and other drugs in this class could prevent or reverse albuminuria. This suspicion 
was strengthened further by the observation that exenatide suppresses the plasma 
concentrations of TGFβ and also suppresses TGFβ signal transduction by reducing the 
expression of SMAD3 and SMAD4. In addition, exenatide also enhances the expression of 
key anti-oxidant enzymes, NQO-1, GST-1P and HO-1, modulated by anti-oxidant response 
elements (ARE) which, in turn, are regulated by the Nrf-2/Keap-1 system. The action of 
this system has now been shown to be protective to the kidney in mouse models of 
experimental diabetes (11). 
 
On the basis of the above, we hypothesized that exenatide and other drugs in this class 
reverse albuminuria. Data from a retrospective analysis on patients with type 2 diabetes 
from our center clearly show that treatment with GLP-1 receptor agonists (mainly 
exenatide and liraglutide) is associated with reductions in the magnitude of albuminuria in 
the entire group. In addition, there was a significant reversal of macroalbuminuria to micro- 
and normoalbuminuria and that of microalbuminuria to normoalbuminuria. In contrast, no 
such changes were observed in patients treated with other anti-diabetic drugs in spite of 
similar glycemic and blood pressure control. 
 
Clearly, therefore, a prospectively randomized study needs to be set up to determine 
whether GLP-1RAs reduce the progression of albuminuria or reverse albuminuria. If 
indeed, this is shown to be true, we shall have an anti-diabetic drug class which for the first 
time will have an effect on the development of microangiopathy in addition to its role as 
an anti-hyperglycemic agent. In this proposal, we intend to investigate the hypothesis that 
treatment of with weekly exenatide reduces the rate of progression of albuminuria in 
patients with type 2 diabetes. 
  
Preliminary data: 
 
1- Effect of GLP-1 RA on evolution of albuminuria in type 2 diabetes: A 
retrospective study. 
Among 466 patients with type 2 diabetes, 70.6 % (n=329) had normoalbuminuria, 24 % 
(n=112) had microalbuminuria and 5.1 % (n=24) had macroalbuminuria. Over a mean 3 
year follow up, there was a reduction in UACR in the entire group by 21.1±328 mg/g from 
a mean of 85.8±374 mg/g to 65.1±225 mg/g. In group A, UACR fell by 37±193 mg/g (from 
87±250 mg/g to 49.8±147 mg/g, p<0.0001), while in group B, UACR increased by 
6±454mg/g (from 81.1±500 mg/g to 87±302 mg/g, p<0.05) (p<0.001 between groups).  
Since there was a significant difference in the reduction of HbA1c between groups A and 
B, we carried out a secondary analysis on UACR differences to adjust for the fall in HbA1c. 
UACR changes from baselines were first log transformed and difference between groups 
were tested with ANCOVA with changes in HbA1c used as a covariate. HbA1c adjusted 
log change in UACR in group A was -0.09±0.49 and in group B was 0.08±0.056 (p=0.007, 
ANCOVA). 


 
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IRB Version: JAN2016 
In the entire cohort (n=466), those with baseline normoalbuminuria (n=329), 88.7 % 
(n=292) remained normal, 10% (n=33) developed microalbuminuria and 1.2% (n=4) 
developed macroalbuminuria. Among those with baseline microalbuminuria (n = 112), 
47.3% (n = 53) regressed to normal, 47.3 % (n =53) remained microalbuminuric, while 5.3 
% (n=6) progressed to macroalbuminuria. Among those with baseline macroalbuminuria 
(n=24), 4% regressed to normal, and 50% regressed to microalbuminuria while 46 % 
remained macroalbuminuric.  
The GLP-1RA users (group A; n =275) were followed up for a mean of 2.3 years. 
(a) Among those who had normoalbuminuria at baseline (n=183), 171 (93.4%) remained 
normal, 10 developed microalbuminuria (5.4%) and 2 developed macroalbuminuria 
(1%) as depicted in Figure 1. The mean UACR changed from 9.4±7.1 mg/g to 18.1±17.2 
mg/g. The mean creatinine concentration changed from 0.98±0.38 mg/dl to 1±0.34 
mg/dl. The eGFR decreased by 5.1±18.4 ml/min from 95.7±31.3 ml/min to 90.7±30.2 
ml/min. The mean HbA1c decreased by 0.7±1.7 % from 7.9±1.7% to 7.2±1.4%. 
(b) Amongst 76 patients who had baseline microalbuminuria, 44 patients (57.8%) 
normalized while 32 (42.1%) remained microalbuminuric during follow up. No patient 
developed macroalbuminuria. The mean UACR fell by 57.7±64.5 mg/g from 
103.5±68.8 mg/g to 45.8±48.7 mg/g, a decrease of 42±74%. The mean creatinine 
changed from 1.04±0.34 to 1.15±0.42 mg/dl. The mean eGFR decreased by 8.6±18 from 
90.2±36.9 ml/min (Table 2).Even in those who remained microalbuminuric, 22 had a 
reduction in UACR of 71.1±54 mg/g from 155.4±74 mg/g to 84.3±55 mg/g. The mean 
HbA1c decreased by 0.8±2.2% from 8.4±2% to 7.6±2% in this group. The 10 patients 
who had no reduction in UACR had a significant increase in HbA1c from 9.2±1.2 % to 
9.7±2.7 %.  
(c) Among the 15 patients who had macroalbuminuria at baseline, 1 normalized (6.6%), 8 
became microalbuminuric (53.3%), and 6 remained macroalbuminuric (40%). The mean 
UACR fell by 500±606 mg/g from 936±579 mg/g to 436±398 mg/g, a decrease of 
40±57%. The mean creatinine increased from 1.37±0.6 mg/dl to 1.47±0.6 mg/dl. The e 
GFR decreased from 76.5±36.5 ml/min to 70.1±34.6 ml/min. The mean HbA1c 
decreased by1±1.2% from 8.4±1.8% to 7.4±1.6%.  
The GLP-1RA non-users (group B; n=191), were followed up for a mean period of 3.6 
years.  
a) 146 patients had normo-albuminuria at baseline. Of these, 121 (82.8%) remained 
normal, 23 (15.7%) developed microalbuminuria and 2 developed macroalbuminuria 
(1.3%). The mean UACR increased by 20.6±81 mg/g from 8.1±6.9 mg/g to 28.7±82.4 
mg/g. The mean creatinine remained stable from 1±0.36 mg/dl to 1.04±0.39 mg/dl. The 
eGFR decreased from 89.1±27.9 ml/min to 87.4±29.5 ml/min. The mean HbA1c 
decreased by 0.4±1.8% from 7.5±1.7% to 7.1±1.4%.  
b) 36 patients had microalbuminuria at baseline. Of these, 9 normalized (25%), 21 
remained microalbuminuric (58.3%) and 6 developed macroalbuminuria (16.6%). The 
mean UACR increased by 60±201 mg/g from 85±48 mg/g to 145±199 mg/g, an 
increase of 105±311%. The mean creatinine changed from 1.06±0.39 mg/dl to 1.2±0.46 
mg/dl. The eGFR decreased by 12.1±15.8 ml/min from 85.3±31.3 ml/min to 73.2±26.7 
ml/min. The mean HbA1c decreased by 0.5±1.6% from 7.8±2.1% to 7.3±1.8%.   
c) 9 patients had baseline macroalbuminuria. Of these, none normalized, 4 became 
microalbuminuric (44.4%), 5 remained macroalbuminuric (55.5%). The mean UACR 


 
Page 10 of 42 
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fell by 453±2085 mg/g from 1248±2075 mg/g to 795±1111 mg/g, a decrease of 
11±98%. The mean creatinine increased from 1.15±0.5 mg/dl to 1.6±0.59 mg/dl. The 
mean eGFR decreased by 30.3±23.3 ml/min from 88.5±47.9 ml/min to 58.2±37.5 
ml/min.  The mean HbA1c decreased by 1.5±3.3% from 9.2±2.9 % to 7.7±1.5%.  
 
Figure 1 below compares the evolution of albuminuria per annum between groups A and 
B.  
 
 
2- Effect of exenatide on Nrf-2/keap-1 system, expression of anti-oxidant enzymes and 
TGFb-1 in MNC. Twenty four obese type 2 diabetics taking insulin were randomized to 
receive either exenatide 10μg twice daily or placebo twice daily for 12 weeks. Fasting 
blood samples were obtained at baseline and 3, 6 and 12 weeks later. Exenatide treatment 
suppressed Keap-1 protein by 21±8% and increased the mRNA expression of NQO-1, 
GST-1P and HO-1 by 51±15%, 42±10% and 39±10%, with an increase in NQO-1 protein 
by 25±10% (p<0.05) in MNC. Exenatide also suppressed plasma TGFβ1 concentrations 
by 20±7% and SMAD-3 expression in MNC by 28±8% (Figure 2, p<0.05).  


 
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Time (Hours)
0
2
4
6
% Change in Keap-1 mRNA in MNC 
70
75
80
85
90
95
100
105
110
115
120
Placebo
Exenatide
 *#
Time (Weeks)
0
3
6
12
% Change in Nrf-2 DNA Binding 
80
90
100
110
120
130
140
150
Placebo
Exenatide 10g
 
Time (Weeks)
0
3
6
12
70
80
90
100
110
120
130
140
150
160
170
Placebo
Exenatide 10g
 *#
Change (%) in NQO-1 mRNA in MNC 
 *#
 *#
Time (Weeks)
0
3
6
12
Plasma TGF (ng/ml)
8
9
10
11
12
13
14
15
16
Placebo
Exenatide 10g
 *#
 
Time (Weeks)
0
3
6
12
% Change in SMAD-3 mRNA in MNC 
60
70
80
90
100
110
120
130
Placebo
Exenatide 10g
 *#
 *#
 *#
 
 
 
 
 
 
 
 
Figure 2: Change in mRNA 
expression of Keap-1, activity of 
Nrf-2, expression of NQO-1 and 
SMAD-3 in MNC and plasma 
concentrations 
of 
TGF-1 
following placebo and exenatide 
10g daily for 12 weeks in type 
2 diabetic subjects. N=12 each, 
data are presented as mean±SE. 
(*: P<0.05 by RMANOVA 
(compared 
to 
baseline), 
#: 
P<0.05 
by 
Two-way 
RMANOVA 
compared 
to 
control groups. 


 
Page 12 of 42 
IRB Version: JAN2016 
3.2 Include complete citations or references.  
Response: 
1. 
Dronavalli S, Duka I, and Bakris GL. The pathogenesis of diabetic nephropathy. 
Nat Clin Pract Endocrinol Metab. 2008;4(8):444-52. 
2. 
Kanwar YS, Sun L, Xie P, Liu FY, and Chen S. A glimpse of various pathogenetic 
mechanisms of diabetic nephropathy. Annu Rev Pathol. 2011;6(395-423. 
3. 
Shankland SJ, Scholey JW, Ly H, and Thai K. Expression of transforming growth 
factor-beta 1 during diabetic renal hypertrophy. Kidney Int. 1994;46(2):430-42. 
4. 
Sharma K, Jin Y, Guo J, and Ziyadeh FN. Neutralization of TGF-beta by anti-TGF-
beta antibody attenuates kidney hypertrophy and the enhanced extracellular matrix 
gene expression in STZ-induced diabetic mice. Diabetes. 1996;45(4):522-30. 
5. 
Osburn WO, and Kensler TW. Nrf2 signaling: an adaptive response pathway for 
protection against environmental toxic insults. Mutat Res. 2008;659(1-2):31-9. 
6. 
Jiang T, Huang Z, Lin Y, Zhang Z, Fang D, and Zhang DD. The protective role of 
Nrf2 in streptozotocin-induced diabetic nephropathy. Diabetes. 2010;59(4):850-60. 
7. 
Assady S, Alter J, Axelman E, Zohar Y, Sabo E, Litvak M, Kaplan M, Ilan N, 
Vlodavsky I, and Abassi Z. Nephroprotective effect of heparanase in experimental 
nephrotic syndrome. PLoS One. 2015;10(3):e0119610. 
8. 
Buse JB, Henry RR, Han J, Kim DD, Fineman MS, and Baron AD. Effects of 
exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated 
patients with type 2 diabetes. Diabetes Care. 2004;27(11):2628-35. 
9. 
DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, and Baron AD. Effects 
of exenatide (exendin-4) on glycemic control and weight over 30 weeks in 
metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28(5):1092-
100. 
10. 
Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, Fineman MS, and 
Baron AD. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in 
patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes 
Care. 2005;28(5):1083-91. 
11. 
Zheng H, Whitman SA, Wu W, Wondrak GT, Wong PK, Fang D, and Zhang DD. 
Therapeutic Potential of Nrf2 Activators in Streptozotocin-Induced Diabetic 
Nephropathy. Diabetes. 2011;60(11):3055-66. 
4.0 
Study Design 
4.1 Describe and explain the study design (e.g. case-control, cross-sectional, 
ethnographic, experimental, interventional, longitudinal, observational). 
Response:  
This is a single center, prospective, double blind, randomized, placebo –controlled in a 
parallel design study. The study will be conducted at the Diabetes – Endocrinology Center 
of Western New York under the direction of Dr. Paresh Dandona, M.D, Dr Manav Batra, 
MD and Dr Husam Ghanim, PhD.   
 
Ninety (90) T2DM patients with micro- or macroalbuminuria (45 each) will be enrolled 
and randomized into 2 groups to receive placebo or exenatide-extended release  treatments 
for 1 year. The study groups and treatment arms of this study are:  


 
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1. T2DM with Microalbuminuria: 30 patients on Exenatide extended release and 15 
patients on placebo for 1 year 
2. T2DM with Macroalbuminuria: 30 patients on Exenatide extended release and 15 
patients on placebo for 1 year 
 
5.0 
Local Number of Subjects 
5.1 Indicate the total number of subjects that will be enrolled or records that will 
be reviewed locally. 
Response: 90 
 
5.2 If applicable, indicate how many subjects you expect to screen to reach your 
target sample (i.e. your screen failure rate).  
Response: All screened and qualified patients will be enrolled and randomized 
 
5.3 Justify the feasibility of recruiting the proposed number of eligible subjects 
within the anticipated recruitment period. For example, how many potential 
subjects do you have access to? What percentage of those potential subjects do 
you need to recruit? 
Response: The Diabetes and Endocrinology Center of WNY is the largest Diabetes 
center in the WNY area, seeing between 100 to 120 type 2  diabetes patients every week. 
Therefore, majority of recruited patients are our Kaleida Health and UBMD clinic 
patients. We will also recruit patients through advertisement, Buffalo Research Registry 
and researchmatch.org. These sources will suffice to recruit the needed number to 
subjects.  
 
6.0 
Inclusion and Exclusion Criteria 
6.1 Describe the criteria that define who will be included in your final study  
6.2 sample.  
NOTE:  This may be done in bullet point fashion. 
Response:  
Inclusion Criteria 
• Type 2 Diabetes for at least 1 year. 
• Microalbuminuria for at least 6 months (UACR: 30-300 mg/g)  
• Macroalbuminuria for at least 6 months (UACR: >300 mg/g)  
• HbA1c of ≤10%  
• Ages 18-65 years (inclusive of ages 18 and 65) 
• On ARBs/ACEi for at >3months 
6.3 Describe the criteria that define who will be excluded from your final study 
sample.   


 
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NOTE:  This may be done in bullet point fashion.  
Response:  
Exclusion Criteria 
• Use of GLP-1 Receptor agonists or SGLT-2 inhibitors therapy in the last 3 
months 
• History or risk for pancreatitis (e.g., history of gallstones, alcohol abuse, and 
hypertriglyceridemia) 
• Coronary event or procedure (myocardial infarction, unstable angina, coronary 
artery bypass, surgery or coronary angioplasty) in the previous 3 months 
• Hepatic disease: Severe hepatic insufficiency and/or significant abnormal liver 
function defined as: 
1. Aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or 
alanine aminotransferase (ALT) >3x ULN 
2. Total bilirubin >2.0 mg/dL (34.2 µmol/L) 
3. Positive serologic evidence of current infectious liver disease including 
Hepatitis B viral antibody IGM, Hepatitis B surface antigen and Hepatitis C 
virus antibody 
4. Liver function tests more than 3 times the upper limit of normal 
• Renal impairment (serum eGFR <30 ml/min) 
• HIV  
• Inability to give informed consent 
• History of gastroparesis  
• History of medullary thyroid carcinoma or MEN 2 syndrome 
• Alcoholism 
• Hypertriglyceridemia (>500 mg/dl). 
• Any other life-threatening, non-cardiac disease 
• Uncontrolled hypertension (BP > 160/100 mm of Hg) 
• Congestive Heart Failure class III or IV 
• Use of an investigational agent or therapeutic regimen within 30 days of study 
• Participation in any other concurrent clinical trial  
• Pregnant or breastfeeding patients or females of childbearing age not on 2 forms of 
acceptable contraceptives. 
 
6.4 Indicate specifically whether you will include any of the following special 
populations in your study using the checkboxes below.   
 
NOTE:  Members of special populations may not be targeted for enrollment in 
your study unless you indicate this in your inclusion criteria. 
Response:  NA 
☐ 
Adults unable to consent 
☐ 
Individuals who are not yet adults (infants, children, teenagers) 


 
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☐ 
Pregnant women 
☐ 
Prisoners 
 
6.5 Indicate whether you will include non-English speaking individuals in your 
study.  Provide justification if you will exclude non-English speaking 
individuals.  
In order to meet one of the primary ethical principles of equitable selection 
of subjects, non-English speaking individuals may not be routinely excluded 
from research as a matter of convenience. 
In cases where the research is of therapeutic intent or is designed to 
investigate areas that would necessarily require certain populations who 
may not speak English, the researcher is required to make efforts to recruit 
and include non-English speaking individuals.  However, there are studies 
in which it would be reasonable to limit subjects to those who speak 
English.  Some examples include pilot studies, small unfunded studies with 
validated instruments not available in other languages, studies with 
numerous questionnaires, and some non-therapeutic studies which offer no 
direct benefit. 
Response: We have no non-English speaking patients in this population.  
We have patients that English is a second language, but they are able to 
read, write and understand it.  This population is less than 10% of the total 
population. 
7.0 
Vulnerable Populations 
If the research involves special populations that are considered vulnerable, 
describe the safeguards included to protect their rights and welfare.   
NOTE: You should refer to the appropriate checklists, referenced below, to ensure you 
have provided adequate detail regarding safeguards and protections. You do not, 
however, need to provide these checklists to the IRB. 
7.1 For research that involves pregnant women, safeguards include: 
NOTE CHECKLIST: Pregnant Women (HRP-412) 
Response: We will not be using subjects from vulnerable populations 
☒ 
N/A:  This research does not involve pregnant women. 
7.2 For research that involves neonates of uncertain viability or non-viable 
neonates, safeguards include: 
NOTE CHECKLISTS: Non-Viable Neonates (HRP-413), or Neonates of Uncertain 
Viability (HRP-414) 
Response:  
☒ 
N/A:  This research does not involve non-viable neonates or neonates of 
uncertain viability. 
7.3 
For research that involves prisoners, safeguards include: 


 
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NOTE CHECKLIST: Prisoners (HRP-415) 
Response:  
☒ 
N/A:  This research does not involve prisoners. 
7.4 For research that involves persons who have not attained the legal age for 
consent to treatments or procedures involved in the research (“children”), 
safeguards include:   
NOTE CHECKLIST: Children (HRP-416) 
Response:  
☒ 
N/A:  This research does not involve persons who have not attained the 
legal age for consent to treatments or procedures (“children”). 
7.5 For research that involves cognitively impaired adults, safeguards include: 
NOTE CHECKLIST: Cognitively Impaired Adults (HRP-417) 
Response:  
☒ 
N/A:  This research does not involve cognitively impaired adults. 
7.6 Consider if other specifically targeted populations such as students, employees 
of a specific firm, or educationally or economically disadvantaged persons are 
vulnerable.  Provide information regarding their safeguards and protections, 
including safeguards to eliminate coercion or undue influence. 
Response: No specific populations or vulnerable groups will be targeted. All 
subjects enrolled in this study will be of legal adult consenting age with the ability 
to speak, read and interrupt the English language. Patients will have the ability to 
speak with the research team regarding any questions or concern they have before 
signing the consent. Patients are made aware that this study is voluntary and they 
are able to stop participating at any time they feel uncomfortable. Patients are not 
be pressured into participating and their clinic standard of care will remain the 
same if they participate or choose not to participate.  
 
8.0 
Eligibility Screening  
8.1 
Describe screening procedures for determining subjects’ eligibility.  Screening 
refers to determining if prospective participants meet inclusion and exclusion criteria.  
Include all relevant screening documents with your submission (e.g. screening 
protocol, script, questionnaire).  
Response:   
After obtaining all necessary approval to conduct the study, study coordinator or 
investigators will conduct a prescreening phone conversation with referred or 
interested patients. Patients will then be schedule for a screening visit. Prospective 
participants will be asked to read and understand the consent and any questions they 
may have regarding the study will be answered. If the subject wants to participate 
in the study, they will be asked to sign the informed consent form. The subject’s 
medical history and current medications will be obtained as well as their blood 
pressure and vitals. Females of childbearing age will be tested for pregnancy and 


 
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asked to sign a commitment form to be on 2 forms of acceptable contraceptives for 
duration of study. A physical examination will also be done. Blood samples will be 
taken in order to evaluate HbA1c, CBC, CMP and liver and kidney functions and 
pregnancy status. Patients meeting all the inclusion and exclusion criteria based on 
all screening tests will be enrolled in the study. 
☐ 
N/A:  There is no screening as part of this protocol. 
9.0 
Recruitment Methods 
☐ 
N/A:  This is a records review only, and subjects will not be 
recruited.  NOTE:  If you select this option, please make sure that 
all records review procedures and inclusion/exclusion screening 
are adequately described in other sections. 
9.1 
Describe when, where, and how potential subjects will be recruited.  
NOTE:  Recruitment refers to how you are identifying potential participants and 
introducing them to the study.  Include specific methods you will use (e.g. 
searching charts for specific ICD code numbers, Research Participant Groups, 
posted advertisements, etc.). 
Response: Potential participants will be identified by prescreening clinical charts, 
patient doctor interaction at the time of their visits. In addition patients will be 
recruited through advertisements , Buffalo Research Registry and 
researchmatch.org. Diabetes Endocrinology Center of WNY Locations include: 
1. 1020 Youngs Road, Williamsville NY 14221 
2. 705 Maple Road, Williamsville NY 14221 
3. 462 Grider Street, Buffalo NY 14215  
The study clinical team will evaluate their clinic patients for possible participation 
in this study according to the inclusion and exclusion criteria at the Diabetes and 
Endocrinology Center of WNY. Patients that may qualify are asked during their 
clinic visits if they are interested in participating in research. Patients that agree 
will be referred to the research team for further eligibility evolution. If these 
patients meeting the inclusion and exclusion criteria based on preliminary phone 
evaluation will be scheduled for a screening visit.  
Facebook and Craigslist will be used for recruitment. The approved advertisement 
will be posted on the main advertising board at Erie County Medical Center. A 
generic flyer will be utilized also for recruiting. 
9.2 Describe how you will protect the privacy interests of prospective subjects 
during the recruitment process.   
NOTE:  Privacy refers to an individual’s right to control access to him or herself.   
Response: Patient charts will be screened according to the study inclusion and 
exclusion criteria by our trained clinical staff and physicians. If the patient 
qualifies and is of consenting age, the physicians will speak to them about their 
interests in participating in research. If the patient agrees, their information will be 
given to the research coordinator to be contacted for further evaluation. Potential 


 
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subjects recruited from advertisement will call the research team for more 
information regarding participating in research.  All personal information will be 
kept confidential and locked in the coordinator office. 
9.3 Identify any materials that will be used to recruit subjects.  
NOTE:  Examples include scripts for telephone calls, in person announcements / 
presentations, email invitations.  
For advertisements, include the final copy of printed advertisements with your 
submission. When advertisements are taped for broadcast, attach the final 
audio/video tape.  NOTE:  You may submit the wording of the advertisement prior 
to taping to ensure there will be no IRB-required revisions, provided the IRB also 
reviews and approves the final version. 
 Response: In addition to screening clinical charts, participations will be identified 
through; advertisement, Buffalo Research Registry, researchmatch.org, 
craigslist.com, and facebook 
10.0 Procedures Involved 
10.1 Provide a description of all research procedures or activities being performed 
and when they are performed once a subject is screened and determined to be 
eligible. Provide as much detail as possible.   
NOTE:  This should serve as a blueprint for your study and include enough detail 
so that another investigator could pick up your protocol and replicate the research.  
For studies that have multiple or complex visits or procedures, consider the 
addition of a schedule of events table in in your response. 
Response:  
 
Visit 1 (week 0):  
Qualifying subjects will be asked to come for the visit in a fasting state (10-12 hr fasting), 
vitals will be done and safety labs for CBC, CMP, HbA1C, kidney function tests will be 
drawn and 24hr urine will be collected. Blood samples (30ml) will be collected for research 
endpoints. Training on administrating study drug and information about side effects and 
how to report any adverse events will be discussed with patients. One of the treatment arms 
will be administered to the patient (placebo or Exenatide extended release in a randomized 
fashion) and enough drug supply for 13+2 weeks will be dispensed. Other diabetes 
medications will be reviewed and any standard of care adjustments will be made. A 24hr 
urine collection container will be dispensed and patients will be instructed to come back 
after 13 weeks. 
 
Visits 2, 3 and 4 (Weeks 13, 26 and 39):  
Patients will come to this visit in the fasting state. Physical exam (only on visit 3) and vitals 
will be performed, safety labs for CBC, CMP, HbA1c, kidney function tests will be drawn 
and 24hr urine collected. Blood samples (30ml) will be collected for research endpoints. 
Other diabetes medications will be reviewed and any standard of care adjustments will be 
made. Study medication use compliance will be assessed and drug supply for 13+2 weeks 
will be dispensed. A 24hr urine collection container will be dispensed and patients will be 
instructed to come back after 13 weeks. 


 
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Visit 5 (Week 52): Patients will come to this visit in the fasting state. Physical exam and 
vitals will be performed, safety labs for CBC, CMP, HbA1c, kidney function tests will be 
drawn and 24hr urine collected. Blood samples (30ml) will be collected for research 
endpoints. Other diabetes medications will be reviewed and any standard of care 
adjustments will be made. Patient will be discharged from the study after the final safety 
phone call at week 56. 
 
Phone call will also be made at weeks 2, 8, 18, 34 and 46 weeks to inforce compliance and 
to ensure safety. Patients will also be instructed to call if they develop unexpected 
symptoms. 
 
LABORATORY PROCEDURES 
 
1. MNC isolation: Blood samples (30-40ml) is collected in Na-EDTA and carefully 
layered on Lympholyte medium (Cedarlane Laboratories, Hornby, ON) according 
to manufacturer’s instructions. Samples are centrifuged and two bands separate out 
at the top of the RBC pellet. The MNC band was harvested and washed twice with 
Hank's balanced salt solution (HBSS). This method provides yields greater than 
95% MNC preparation. 
2. ROS generation measurement by chemiluminescence: Five hundred L of 
MNC (2 x 105 cells) are delivered into a Chronolog LumiAggregometer cuvette. 
Luminol is then added, followed by 1.0 L of 10 mM formylmethionyl leucinyl 
phenylalanine (fMLP).  Chemiluminescence is recorded for 15 minutes. In this 
assay system, the release of superoxide radical as measured by chemiluminescence, 
has been shown to be linearly correlated with that measured by the ferricytochrome 
C method.  The interassay coefficient of variation of this assay is 8 %. We have 
further established that the biological variation in reactive oxygen species 
generation in normal subjects is approximately 6 % for readings obtained 1 to 2 
weeks apart. Similarly, the variation in reactive oxygen species generation in the 
obese over a period of 1 to 2 weeks is less than 8 %. 
3.  Quantification of p47phox, Keap-1, NQO-1, GST-1P, HO-1 and SMADs 2-4 
expression: The mRNA expression is measured in MNC by RT-PCR: Total RNA 
was isolated using commercially available RNAqueous®-4PCR Kit (Ambion, 
Austin, TX). One µg of total RNA is reverse transcribed using Advantage RT-for-
PCR Kit (Clontech, CA). Real Time RT-PCR was performed using Stratagene 
Mx3000P QPCR System (La Jolla, CA), Sybergreen master mix (Qiagen, CA) and 
gene specific primers (Life Technologies, MD). All values were normalized to the 
expression of a group of housekeeping genes including actin, ubiquitin C and 
cyclophilin A. 
4.  Western blotting: MNC total cell lysates are prepared and proteins separated by 
SDS-PAGE and then transferred to PVDF membrane. Polyclonal or monoclonal 
antibodies against p47phox, Keap-1, Nrf-2, SMADs and NQO-1 (Abcam, 
Cambridge, MA) and actin (Santa Cruz Biotechnology, CA) will be used. 
Densitometry is performed using molecular analyst software (Biorad, CA) and all 
values are corrected for loading with actin. 


 
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5. Nrf-2 DNA binding: Nuclear Nrf-2 DNA binding activity will be measured by 
EMSA. Nuclear extract is prepared from freshly tissues by NE-PER® Nuclear 
Extraction kit (Pierce Biotechnology, Rockford, IL). The specificity of the bands 
is confirmed by supershifting these bands with specific antibodies against Nrf-2 
(Santa Cruz Biotechnology, CA) and by competition with cold oligonucleotides. 
DNA binding activity of Nrf-2 will be adjusted to Oct-1 DNA binding activity to 
correct for technical variables.  
6. Plasma measurements: Glucose levels are measured in plasma by YSI 2300 
STAT Plus glucose analyzer (Yellow Springs, Ohio). ELISA kits will be used to 
measure insulin (Millipore, MA), TGF-b1, CTGF, TIMPs, PAI-1 (R&D Systems), 
type I and IV collagen and fibronectin (fibronectin EDA). HbA1c, serum creatinine 
and cystatin C will measured by standard assays by Quest Diagnostic Labs. 
7. Urinary measurements: Albuminuria, creatinine, creatinine clearance, GFR will 
measured from 24hr urine collection by standard assays by Quest Diagnostic Labs. 
8. 15-isoprostane F2t (also known as 8-epi-PGF2α or 8-iso-PGF2α) in urine samples 
will be measured by an ELISA kit from Oxford Biomedical Research (Oxford, MI). 
 
10.2 Describe what data will be collected.   
NOTE:  For studies with multiple data collection points or long-term follow up, 
consider the addition of a schedule or table in your response. 
Response:  
The study investigations include evaluation of the effects of 1-year treatment with 
Exenatide extended release or placebo on progression of albuminuria and related kidney 
function measures in T2DM patients with established micro- or macroalbuminuria. 
Qualified patients will come fasting to the research center. Review of study procedures and 
vitals will be performed. Basal blood and 24-urine samples will be obtained. Patients will 
be randomized (in 2:1 ratio) to receive either Exenatide extended release or placebo for 1 
year. Plasma and mononuclear cell (MNC) fractions will be prepared from the blood 
samples. Additional fasting blood and 24hr urine samples will be collected every 13±2 
weeks (3, 6, 9 and 12 months) for a total of 5 study visits. Measurements of albuminuria, 
creatinine, creatinine clearance, GFR, isoprostanes and cystatin C following 1-year 
treatment with Exenatide extended release or placebo will be done on all urine samples 
collected before and at 3, 6, 9 and 12 months following treatment with Exenatide extended 
release or placebo. HbA1c, CBC, CMP, TGFβ, type I and IV collagen, CTGF, PAI-1, 
TIMP-1 and 2 and fibronectin EDA levels will be measured in all plasma samples collected 
while the expression of SMAD3, SMAD4, NQO-1, GST-1P and HO-1, Nrf-2/keap-1 
system activation, p47phox levels and ROS generation will be done in all MNC samples 
collected before and at 13, 26, 39 and 62 weeks following treatment with Exenatide 
extended release or placebo.  
 
Visit # 
Screening 
1 
2 
3 
4 
5 
Weeks # 
<-4 
0 
13±2 
26±2 
39±2 
52±2 
Medical History 
X 
 
 
 
 
 
Physical exam 
X 
 
 
X 
 
X 


 
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CBC/CMP/kidney function 
X 
X 
X 
X 
X 
X 
Vitals and BP 
X 
X 
X 
X 
X 
X 
Pregnancy test 
X 
 
X 
X 
X 
X 
HbA1c 
X 
X 
X 
X 
X 
X 
MNC endpoints 
X 
X 
X 
X 
X 
Plasma mediators endpoints 
 
X 
X 
X 
X 
X 
Urinary endpoints 
 
X 
X 
X 
X 
X 
Other diabetes medications 
review and adjustments  
 
X 
X 
X 
X 
X 
 
10.3 List any instruments or measurement tools used to collect data 
(e.g. questionnaire, interview guide, validated instrument, data collection 
form).  
Include copies of these documents with your submission. 
Response: Source documents will be used to collect patient information.  Food 
and glucose measurement diaries will be also reviewed for medication 
adjustment. 
10.4 Describe any source records that will be used to collect data about subjects 
(e.g. school records, electronic medical records). 
Response: electronic medical records and research files. 
10.5 Indicate whether or not individual subject results, such as results of 
investigational diagnostic tests, genetic tests, or incidental findings will be 
shared with subjects or others (e.g., the subject’s primary care physician) and 
if so, describe how these will be shared. 
Response: Individual participant lab results will be disclosed to the participant 
upon their request. If the participant requests documentation be shared with 
another physician, physician office or hospital the participant must come to the 
research center to collect said documentation or the documentation can be mailed 
to their given home address. 
10.6 Indicate whether or not study results will be shared with subjects or others, 
and if so, describe how these will be shared. 
Response: Not Applicable. Study results will not be shared with the subjects. 
However, unidentifiable study results could be published in the form of a 
manuscript or abstract and will be reported to Astra Zeneca and to 
clinicaltrials.gov 
11.0 Study Timelines 
11.1 Describe the anticipated duration needed to enroll all study subjects. 


 
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Response: Enrollment of 90 patients should be completed within 10 months at a rate of 9 
patients/month. 
11.2 Describe the duration of an individual subject’s participation in the study. 
Include length of study visits, and overall study follow-up time. 
Response: 52 Weeks 
11.3 Describe the estimated duration for the investigators to complete this study 
(i.e. all data is collected and all analyses have been completed). 
Response: Approximately 30 Months 
12.0 Setting 
12.1 Describe all facilities/sites where you will be conducting research procedures.  
Include a description of the security and privacy of the facilities (e.g. locked 
facility, limited access, privacy barriers).  Facility, department, and type of 
room are relevant.  Do not abbreviate facility names.   
NOTE:  Examples of acceptable response may be:  “A classroom setting in the 
Department of Psychology equipped with a computer with relevant survey 
administration software,” “The angiogram suite at Buffalo General Medical 
Center, a fully accredited tertiary care institution within New York State with 
badge access,” or, “Community Center meeting hall.” 
Response: Research will be conducted at the Diabetes Endocrinology Research 
Center of WNY, located at 1000 Youngs Rd, Suite 105, Williamsville, NY 14221 
and at the CTRC located in 875 Ellicott St. Buffalo NY14203.The Diabetes Research 
Center has facilities and exam rooms available for insulin pump download, CGM 
device download, meal and infusion studies and presence of study coordinator and 
registered nurse for data collection and blood work at all times. One of the 
investigators will be available at all times to address patients’ related issues. 
CTRC location is a fully equipped laboratory with equipment include ultra-low 
freezers for sample storage, centrifuges, microscopes for sample preparation, 
infusion pumps, ELISA, PCR and immunoblotting instrumentation.  
12.2 For research conducted outside of UB and its affiliates, describe: 
• Site-specific regulations or customs affecting the research 
• Local scientific and ethical review structure 
NOTE:  This question is referring to UB affiliated research taking place outside 
UB, i.e. research conducted in the community, school-based research, 
international research, etc.  It is not referring to multi-site research.  UB affiliated 
institutions include Kaleida Health, ECMC, and Roswell Park Cancer Institute.   
Response:  
☒ 
N/A:  This study is not conducted outside of UB or its affiliates. 
13.0 Community-Based Participatory Research 


 
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13.1 Describe involvement of the community in the design and conduct of the 
research.  
NOTE:  Community-Based Participatory Research (CBPR) is a collaborative 
approach to research that equitably involves all partners in the research process 
and recognizes the unique strengths that each brings.  CBPR begins with a 
research topic of importance to the community, has the aim of combining 
knowledge with action and achieving social change to improve health outcomes 
and eliminate health disparities. 
Response:  
☒ 
N/A:  This study does not utilize CBPR. 
13.2 
Describe the composition and involvement of a community advisory 
board. 
Response:  
☒ 
N/A:  This study does not have a community advisory board. 
14.0 Resources and Qualifications 
14.1 Describe the qualifications (e.g., education, training, experience, expertise, or 
certifications) of the Principal Investigator and staff to perform the research.  
When applicable describe their knowledge of the local study sites, culture, and 
society.  Provide enough information to convince the IRB that you have 
qualified staff for the proposed research.  
NOTE:  If you specify a person by name, a change to that person will require prior 
approval by the IRB.  If you specify a person by role (e.g., coordinator, research 
assistant, co-investigator, or pharmacist), a change to that person will not usually 
require prior approval by the IRB, provided that the person meets the 
qualifications described to fulfill their roles. 
Response: All study personnel are educated, trained, and licensed as required for 
their delegated role in this study.  All study personnel have also received the 
required university training and will be trained by the PI before the study starts 
 
Describe other resources available to conduct the research.  
14.2 Describe the time and effort that the Principal Investigator and research staff 
will devote to conducting and completing the research. 
NOTE:  Examples include the percentage of Full Time Equivalents (FTE), hours 
per week.  The question will elicit whether there are appropriate resources to 
conduct the research. 
Response: The principal investigator supervises the research project and weekly research 
meetings are conducted to discuss the recruitment rate, resolve and discuss issues related 
to the conduct, safety, analysis of the study and related publications. PI is expected to 
spend 5% of his academic time on this research. The co-investigators and study 
coordinator provide coverage to the research related activity for 365 days a year. 


 
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14.3 Describe the availability of medical or psychological resources that subjects 
might need as a result of anticipated consequences of the human research, if 
applicable. 
NOTE:  One example includes: on-call availability of a counselor or psychologist 
for a study that screens subjects for depression. 
Response: Available medical literature will be provided as deemed appropriate or 
requested by patient through UB libraries, PubMed, Google scholar as all the 
investigators have access to medical literature through listed resources above. The patient 
will also have access to physician (Investigators and Co-Investigators) who will be 
available to address any adverse effects or other questions during the course of the study 
and make the appropriate referrals.  
14.4 Describe your process to ensure that all persons assisting with the research 
are adequately informed about the protocol, the research procedures, and their 
duties and functions. 
Response: Education through training meetings, conferences and discussions. Training 
records will be kept by study coordinator and updated when following any amendments 
15.0 Other Approvals 
15.1 Describe any approvals that will be obtained prior to commencing the 
research (e.g., school, external site, funding agency, laboratory, radiation 
safety, or biosafety). 
Response: NA 
☒ 
N/A:  This study does not require any other approvals. 
16.0 Provisions to Protect the Privacy Interests of Subjects 
 
16.1 Describe how you will protect subjects’ privacy interests during the course of 
this research. 
NOTE:  Privacy refers to an individual’s right to control access to him or herself.  
Privacy applies to the person.  Confidentiality refers to how data collected about 
individuals for the research will be protected by the researcher from release.  
Confidentiality applies to the data.   
Examples of appropriate responses include:  “participant only meets with a study 
coordinator in a classroom setting where no one can overhear”, or “the 
participant is reminded that they are free to refuse to answer any questions that 
they do not feel comfortable answering.”   
Response:  
When the patient is being seen at our outpatient clinics for the first time they sign the 
“Consent to use and disclosure of protected health information” form which clearly states 
that their protected health information (PHI) can be used for review in preparation for 
possible research. 
Our clinical providers involved in the study will identify potential patients for recruitment 
from the Diabetes-Endocrinology Center of WNY Clinics according to the inclusions and 


 
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exclusion criteria and through advertisements. Patient who may qualify will be asked in 
private during their one on one consultation time with the physician if they wish to 
participate in the research study. If the patient agrees, the research coordinator will 
contact them for a telephone screening interview privately. During phone conversation, 
no private information will be spoken loudly by study staff conducting the interview. The 
patients who call for potential participation in the study due to advertisement flyers will 
be screened over the phone with the research coordinator, using our telephone screening 
form.  All records of this telephone interview will be kept in the study binder locked in 
the research unit. 
If the patient passes the telephone screening, they will be asked to make an appointment 
to review the consent. Patient will do this in a private, screen off area of the research 
department and will be allowed to discuss the consent in detail with the research 
coordinator and or study doctor. Patient will be notified that it is completely voluntary to 
participate in the research study and can withdraw at any time. 
We will not be accessing any medical information of the patients for whom the services 
are not provided by our clinic providers. 
16.2 Indicate how the research team is permitted to access any sources of 
information about the subjects.   
NOTE:  Examples of appropriate responses include:  school permission for review 
of records, consent of the subject, HIPAA waiver.  This question does apply to 
records reviews. 
Response: Consent of the subject and partial HIPAA waiver. 
17.0 Data Management and Analysis 
17.1 Describe the data analysis plan, including any statistical procedures.  This 
section applies to both quantitative and qualitative analysis.  
Response: DATA ANALYSIS  
This is a prospective study to evaluate effect of Exenatide extended release treatment for 
1 year  on albuminuria levels in T2DM patients with micro- and macroalbuminuria 
compared to placebo. The similarities in baseline values between the study groups will be 
compared using appropriate parametric tests. Transformations of the data on order to meet 
statistical assumptions may be considered. All statistical analysis will be carried out using 
SPSS software (SPSS Inc, Chicago, Illinois) based on intention to treat principle. Data 
will be presented as mean±standard error. The primary endpoint of the study is the change 
from baseline in albuminuria level at weeks 12, 26, 39 and 56 following Exenatide 
extended release and placebo treatments. Fasting samples collected at weeks 0, 12, 26, 39 
and 56 will be used for this assessment with values at week 0 considered as baseline. 
Changes from baselines form both drugs arms will be compared to those from the placebo 
arms in both the micro and macroalbuminuria groups. The statistical analysis will be done 
using mixed model for repeated measurement (MMRM) analysis with assigned α value 
of 0.05. Our preliminary data on retrospective analysis of the difference in albuminuria 
following GLP-1RA treatment for 2.5 yrs in T2DM patients with micro and 
macroalbuminuria show regression of albuminuria (UACR) by approximately 55mg/mg 
and 500mg/g (about 50% reduction), respectively.  


 
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The secondary end points include the comparison of the changes in albuminuria based on 
baseline albuminuria category (micro or macro), creatinine clearance, Cystatin C, TGFβ, 
type I and IV collagen, CTGF, and fibronectin levels, the expression of SMAD3, SMAD4, 
NQO-1, GST-1P and HO-1, Nrf-2/keap-1 system activation between the Exenatide 
extended release and placebo groups and across albuminuria categories 
 
17.2 If applicable, provide a power analysis.   
NOTE:  This may not apply to certain types of studies, including chart/records 
reviews, survey studies, or observational studies.  This question is asked to elicit 
whether the investigator has an adequate sample size to achieve the study 
objectives and justify a conclusion.  
Response:. Conservatively estimating a difference in the change from baseline in 
albuminuria after 1 year between the Exenatide extended release and placebo groups 
(across both albuminuria groups) of 60mg/g, with standard deviation of no more than 
91mg/g, a sample size of 38 patients per group should provide adequate power ( = 0.2) 
to detect a significant difference ( = 0.05). Aassuming a drop-out rate of 15% and 2:1 
drug: placebo randomization ratio, 60 active and 30 control will be recruited for a total 
of 90 patients (rounded up). Patients will be enrolled based on a predetermined 
stratification according to the two albuminuria categories (micro and macro at 1:1 ratio) 
with 45 patients in each. 
 
17.3 Describe any procedures that will be used for quality control of collected data. 
 
Response: Three investigators and research nurse will double check the accuracy 
of collected data. All laboratory testing will be standardized using references and 
standards. 
18.0 Confidentiality 
 
A. Confidentiality of Study Data 
 
Describe the local procedures for maintenance of confidentiality of study data 
and any records that will be reviewed for data collection.   
 
18.1 
A.  Where and how will all data and records be stored?  Include 
information about:  password protection, encryption, physical controls, 
authorization of access, and separation of identifiers and data, as applicable.  
Include physical (e.g. paper) and electronic files. 
Response: All patients’ data records will be stored on password protected 
computers and or in locked cabinets within the research department. The research 
unit is locked after 5pm daily and all day on weekends. Identifiable patient 
information along with randomization information for each patient will be stored 
in locked cabinets in an locked archive room. This will only be accessible by 


 
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study coordinator and the PI. Electronic data will be stored on password protected 
computers as coded data based on randomization number eg R-12 without any 
patients identifiable information attached. These electronic files will only be 
accessible by authorized study personnel. 
18.2 
A.  How long will the data be stored? 
Response: Data and specimens storage has no expiration date and will be stored for a 
minimum of 7 years. The researchers may continue to rely on this for future use in 
research study 
18.3 
A.  Who will have access to the data? 
Response: Those physicians, nurses, and laboratory staff that are on all 
documentation for the study will have access to the data. 
18.4 
A.  Who is responsible for receipt or transmission of the data? 
Response: Those physicians, nurses, and laboratory staff that are on all 
documentation for the study will have access to the data and can handle transfer 
of data. 
18.5 
A.  How will the data be transported? 
Response: All data are stored at one location and is not transported unless it is 
being archived. At that point files will be transferred to Iron Mountain for storage 
and archiving.  
B. Confidentiality of Study Specimens 
 
Describe the local procedures for maintenance of confidentiality of study 
specimens.   
 
☐ 
N/A:  No specimens will be collected or analyzed in this research.   
(Skip to Section 19.0) 
 
18.6 
B.  Where and how will all specimens be stored?  Include information 
about:  physical controls, authorization of access, and labeling of specimens, as 
applicable.   
Response: The specimens will be stored in the CRC laboratory located at 1000 
Youngs Road, Suite 105, Williamsville NY 14221 and at the CTRC located in 875 
Ellicott St. Buffalo NY14203. Samples will be stored in a locked -80o C freezers. 
Ultimately, all specimens will be transported to CTRC location for banking. 
Specimens will be labeled as a coded sample, using the patient’s randomization 
number (e.g. R-12), visit time and number and sample type. Specimens will not 
be stored with any patient identifiable information which is kept in locked 
cabinets in the CRC at Youngs Rd. 
18.7 
B.  How long will the specimens be stored? 
Response: Specimens storage has no expiration date and will be stored for a minimum of 
7 years. The researchers may continue to rely on this for future use in research studies. 


 
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18.8 
B.  Who will have access to the specimens? 
Response: Those physicians, nurses, and laboratory staff that are on all 
documentation for the study will have access to the specimens. 
18.9 
B.  Who is responsible for receipt or transmission of the specimens? 
Response: Those physicians, nurses, and laboratory staff that are on all 
documentation for the study will have access to the specimens and can handle 
transfer of samples. 
18.10 B.  How will the specimens be transported? 
Response: Fresh samples collected for screening and safety will be transported by 
Quest Diagnostics courier at ambient temperature and according to Quest 
Diagnostics instructions. Frozen samples that are transported will be done so 
using dry ice in a properly labeled Styrofoam container by the laboratory 
technician. 
 
19.0 Provisions to Monitor the Data to Ensure the Safety of Subjects 
☐ 
N/A:  This study is not enrolling subjects, or is limited to records review 
procedures only.  This section does not apply. 
 
NOTE:  Minimal risk studies may be required to monitor subject safety if the research 
procedures include procedures that present unique risks to subjects that require 
monitoring.  Some examples include:  exercising to exertion, or instruments that elicit 
suicidality or substance abuse behavior.  In such cases, N/A is not an acceptable 
response. 
 
19.1 Describe the plan to periodically evaluate the data collected regarding both 
harms and benefits to determine whether subjects remain safe. 
Response: The principal investigator Paresh Dandona, MD, PhD and co-
investigators, Manav Batra, MD and Husam Ghanim, PhD will review the data at 
the completion of all visits off each subject and every 3 months to assess the safety 
and any potential risks or benefits to the participants. Furthermore they will also 
assess other risks including the physical, psychological, social, legal and economic 
harm to these patients. The investigators listed above will carefully watch for any 
invasion of privacy and breach of confidentiality. The principal investigator will be 
sharing the results of safety analysis of the study with AZ and with the IRB. The 
study groups will remain blinded. If there are any safety concerns then co-
investigator Husam Ghanim, PhD who is not directly involved with the study 
participants will unblind the study groups on the discretion of principal investigator 
and tabulate and present unblinded data to the investigators for review. Based on 
review of the data presented, assessment of potential harm to the patients will be 
carried out to determine the best course of action. The IRB and sponsor will be 
informed of this potential harm along with the recommended course of action. 
Research subjects will be withdrawn from the study if risks are significant and/or 


 
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not manageable (see subject withdrawal section). The IRB will be kept well-
informed at all times. 
19.2 Describe what data are reviewed, including safety data, untoward events, and 
efficacy data. 
Response Safety data (vitals, CBC, CMP, urinary markers) will be collected at 
screening, during and at end of the study. Injection site reactions and hypoglycemia 
data will be monitored and collected at every visit. Physical examination will be 
performed at 26 and 52 weeks visits and safety assessments performed. Pregnancy 
results and contraceptive adherence plan (if applicable) will be reviewed at 
screening, 16 and 39 and 52 weeks.  
  
19.3 Describe any safety endpoints. 
Response: N/A. 
19.4 Describe how the safety information will be collected (e.g., with case report 
forms, at study visits, by telephone calls with participants). 
Response: The safety information will be collected at the time of the participants 
visit, and or during telephone calls with the participant using source documents. 
19.5 Describe the frequency of safety data collection. 
Response: The data collection will be done at all study visits which will be at 
intervals of either one or two weeks depending on the number of study visit. The 
patients, however, will be asked to report any adverse event or safety related 
information via phone as soon as it occurs and it will be reviewed the same day. 
19.6 Describe who will review the safety data. 
Response:  The principal investigator Paresh Dandona, MD, PhD and co-investigators, 
Manav Batra, MD and Husam Ghanim, PhD will review the data at the completion of all 
visits by each subject and every 3 months to assess the safety and any potential risks to 
the participants.  
19.7 Describe the frequency or periodicity of review of cumulative 
safety data. 
Response: Every 3 months, Dr. Dandona, Dr. Batra and Dr. Ghanim will assess the safety 
and any potential risks to the participants. Safety data (vitals, CBC, CMP, urinary markers) 
will be collected at screening, during and at end of the study. Injection site reactions and 
hypoglycemia data will be monitored and collected at every visit.  Physical examination 
will be performed at 26 and 52 weeks visits and safety assessments performed. Pregnancy 
(if applicable) will be tested at screening, 16 and 39 and 52 weeks. Oral anti-hyperglycemic 
agents and/or insulin dose titration will be done to avoid hypoglycemia. Phone calls will 
be made for safety and compliance follow-up at least 6 time during the study. The patients, 
however, will be instructed to report any adverse event or safety related information via 
phone as soon as it occurs. All safety data will be reviewed by the PI or sub-investigators 
within 1-2 days of collection. 
 


 
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19.8 Describe the statistical tests for analyzing the safety data to determine whether 
harm is occurring. 
Response: The statistical analysis will be carried out using the student t-test or 
Wilcoxson’s test for paired data. 
19.9 Describe any conditions that trigger an immediate suspension of the research. 
Response:  
1. New safety information becoming available concerning the safety of study 
drugs. 
2. Termination of funding. 
3. Withdrawal of study drug by FDA 
4. Significant increase in risks (beyond expected risks) based in review of safety 
data.  
20.0 Withdrawal of Subjects 
☐ 
N/A:  This study is not enrolling subjects.  This section does not apply. 
 
20.1 Describe anticipated circumstances under which subjects may be withdrawn 
from the research without their consent. 
Response: The principal investigator of the study can remove a participant from the 
research study without their approval if for any reason he/she feels is appropriate, 
including 
i. 
Pregnancy 
ii. 
Developing conditions included in the exclusion criteria 
iii. Subjects decision to withdraw from the study 
iv. Severe side effects specific to study drugs 
v. 
Any medical condition that may place patient at risk of further complications 
vi.  failure to take the medication as instructed, failure to keep your scheduled 
appointments, 
vii.  cancellation of the study by the sponsor, or other administrative reasons. 
20.2 Describe any procedures for orderly termination.   
NOTE:  Examples may include return of study drug, exit interview with clinician.  
Include whether additional follow up is recommended for safety reasons for 
physical or emotional health. 
Response: If a subject withdraws from the research, the data collected to 
that point will be used toward the research finding. If applicable the 
subject will have to bring back any unused research drug and or device. If 
necessary, they will be asked to complete an end of study visit for their 
safety.   
20.3 Describe procedures that will be followed when subjects withdraw from the 
research, including retention of already collected data, and partial withdrawal 
from procedures with continued data collection, as applicable. 


 
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Response: If a subject withdraws from the research, the data collected to that 
point will be used toward the research finding. If applicable the subject will have 
to bring back any unused research drug and or device. If necessary, they will be 
asked to complete an end of study visit for their safety.   
21.0 Risks to Subjects 
21.1 List the reasonably foreseeable risks, discomforts, hazards, or inconveniences 
to the subjects related to their participation in the research. Consider physical, 
psychological, social, legal, and economic risks.  Include a description of the 
probability, magnitude, duration, and reversibility of the risks.  
NOTE:  Breach of confidentiality is always a risk for identifiable subject data. 
Response:  
All subjects will be referred to exenatide and extended release exenatide labeling safety 
information and discussions of the potential side effects and the different warning and 
precautions will take place at the time of signing the informed consent and prior to 
treatment.  
Potential side effects of GLP-1 agonist include hypotension, nausea, vomiting and other 
GI side effects. Patients will be provided guidance on potential side effects and how to 
properly manage and report it. The potential benefits including improved glycemia, 
improved BP, potential renal protection, improved quality of life (QOL) will most probably 
overcome the potential side effects. 
Exenatide extended release caused rats to develop tumors of the thyroid gland. Some of 
these tumors were cancer. It is not known if Exenatide extended release will cause thyroid 
tumors or a type of thyroid cancer called medullary thyroid cancer in people. This will be 
discussed in details with all participating subjects. Exenatide is contraindicated in patients 
with a personal or family history of MTC and in patients with Multiple Endocrine 
Neoplasia syndrome type 2 (MEN 2).  
Injection-site reactions: Serious injection-site reactions, with or without bumps (nodules), 
have happened in some people who use exenatide extended release. Some of these 
injection-site reactions have required surgical intervention. Report any injection site 
reactions including nodules to study investigators.  
Severe allergic reaction (anaphylaxis) to study drugs or placebo ingredients or other 
interventions may accrue in rare cases. Epinephrine is the primary treatment for 
anaphylaxis with no absolute contraindication to its use. Our site and staff are trained and 
equipped to assist patients with such reactions. Severe conditions that are not satisfactory 
managed in site will be transferred to the hospital emergency department for further 
assessment and help. 
All subjects will be informed of the potential complication of administration a blood draw, which 
includes mild bruising at the site . This should resolve in few days 
Breach of confidentiality is always a risk. However, to minimize this risk patient data will be coded 
using a unique identification number and the data will only accessible to the study 
personnel. 
 


 
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21.2 Describe procedures performed to lessen the probability or magnitude of risks, 
including procedures being performed to monitor subjects for safety. 
Response: Patients will be instructed to call the Diabetes Center to speak to a study 
investigator directly in case of any problem or untoward side effects. Pregnancy (if 
applicable) will be tested at screening, 16 and 39 and 52 weeks. Oral anti-hyperglycemic 
agents and/or insulin dose titration will be done to avoid hypoglycemia. Phone calls will 
be made for safety and compliance follow-up at least 6 time during the study. The patients, 
however, will be instructed to report any adverse event or safety related information via 
phone as soon as it occurs. All adverse events will be reviewed by the PI or sub-
investigators within 24 hr of reporting and all safety data will reviewed every 3 months. 
 
21.3 If applicable, indicate which procedures may have risks to the subjects that 
are currently unforeseeable. 
Response:  
Any adverse effects of Exenatide not currently known or those unique to 
their use in Type 2 diabetes with diabetic kidney disease may be some of 
the unforeseeable risks. 
21.4 If applicable, indicate which research procedures may have risks to an embryo 
or fetus should the subject be or become pregnant. 
Response: Not applicable, we will not be enrolling pregnant participants or who 
may become pregnant or with in child baring years without signing the consent 
stating they will use at least two forms of birth control. If a participant becomes 
pregnant they will be withdrawn from the study immediately.  
21.5 If applicable, describe risks to others who are not subjects. 
Response: Not applicable, there is no risk to others not participating in this study. 
22.0 Potential Benefits to Subjects 
22.1 Describe the potential benefits that individual subjects may experience by 
taking part in the research.  Include the probability, magnitude, and duration 
of the potential benefits.  Indicate if there is no direct benefit.   
NOTE:  Compensation cannot be stated as a benefit. 
Response: Exenatide LR is approved for treatment of Type 2 diabetes and has 
beneficial effects on glycemic control and weight. Subjects will also benefit from 
close monitoring of their renal disease.. 
23.0 Compensation for Research-Related Injury 
☐ 
N/A:  The research procedures for this study do not present risk of 
research related injury (e.g. survey studies, records review studies).  This 
section does not apply.   
23.1 
If the research procedures carry a risk of research related injury, 
describe the available compensation to subjects in the event that such injury 
should occur.   


 
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Response: Routinely, Buffalo General Hospital, Erie County Medical Center, 
and/or the University at Buffalo, State University of New York, its agents, or its 
employees do not compensate for or provide free medical care for human 
subjects/participants in the event that any injury results from participation in a 
human research project.  In the unlikely event that they become ill or injured as a 
direct result of participating in this study, they may receive medical care, that will 
be covered by study. 
23.2 
Provide a copy of contract language, if any, relevant to compensation for 
research related injury. 
NOTE:  If the contract is not yet approved at the time of this submission, submit the 
current version here.  If the contract is later approved with different language regarding 
research related injury, you must modify your response here and submit an amendment 
to the IRB for review and approval. 
Response: AstraZeneca shall reimburse the Institution for the direct, reasonable and 
necessary medical expenses incurred by the Institution for the treatment of any 
personal injury that is a direct result of adverse drug experiences to subjects 
resulting directly from any manufacturing defects in the Study Drug to which the 
Subjects would not have been exposed but for their participation in the Study if (i) the 
Institutional parties have complied with this Agreement, the Protocol and any written 
instructions of AstraZeneca concerning the Study Drug and (ii) all the requirements 
of informed consent have been complied with. AstraZeneca will not provide 
compensation for lost wages or for any other damages, expenses or losses, or for 
medical expenses that have been covered by a Subject’s medical or other insurance. 
 
24.0 Economic Burden to Subjects 
24.1 Describe any costs that subjects may be responsible for because of 
participation in the research.   
NOTE:  Some examples include transportation or parking. 
Response: All research expenses will be covered. Participants will not be 
subjected to any out of pocket cost.  
☐ 
N/A:  This study is not enrolling subjects, or is limited to records review 
procedures only.  This section does not apply. 
25.0 Compensation for Participation 
25.1 
Describe the amount and timing of any compensation to subjects, 
including monetary, course credit, or gift card compensation. 
Response:  
Total compensation for this study will be up to $400.00 after the completion of all 
study visits. Each completed study visit will be paid at $80.00. There is a total of 5 
study visits. This payment will be received in the form of a check to the study 
participant. 


 
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☐ 
N/A:  This study is not enrolling subjects, or is limited to records 
review procedures only.  This section does not apply. 
☐ 
N/A:  There is no compensation for participation.  This section 
does not apply. 
26.0 Consent Process 
26.1 Indicate whether you will be obtaining consent.   
NOTE:  This does not refer to consent documentation, but rather whether you will 
be obtaining permission from subjects to participate in a research study.   
Consent documentation is addressed in Section 27.0. 
☒ 
Yes 
(If yes, Provide responses to each question in this Section) 
☐ 
No 
(If no, Skip to Section 27.0) 
 
26.2 Describe where the consent process will take place.  Include steps to maximize 
subjects’ privacy. 
Response: All participants will come to the research department to be consented. 
Participants will be placed in a private, screened off area and or room where they 
can review the consent. Participant questions and or concerns will be address with 
a member of the study team or research doctor if applicable. The research 
coordinator will discuss in length the participants requests for privacy of their 
PHI.  
26.3 Describe how you will ensure that subjects are provided with a sufficient 
period of time to consider taking part in the research study.   
NOTE:  It is always a requirement that a prospective subject is given sufficient 
time to have their questions answered and consider their participation.  See “SOP: 
Informed Consent Process for Research (HRP-090)” Sections 5.5 and 5.6. 
Response: participants will be made aware that participating in research is 
completely voluntary, and they may withdraw at any time with no consequence to 
their routine clinic care. If the patients requires time to decide and or discuss 
partaking in a research study, the subject will be given said time.  
26.4 Describe any process to ensure ongoing consent, defined as a subject’s 
willingness to continue participation for the duration of the research study.   
Response: The research coordinator and study team are available to answer any 
question or concerns with the patient during the duration of the research trial. At 
each study visit, the patient is asked a series of questions to ensure they are on 
task with the study visits and feel comfortable. Upon departing from their study 
visit, the patients are told of their next visit and given detail instruction for their 
next visit. If study is revised or amendment or new information becomes available 
about drug safety that may affect patients participation, the patient may be re-
consented to ensure patient ongoing consent. 


 
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26.5 Indicate whether you will be following “SOP: Informed Consent Process for 
Research (HRP-090).” If not, or if there are any exceptions or additional 
details to what is covered in the SOP, describe: 
• 
The role of the individuals listed in the application who are involved in 
the consent process 
• 
The time that will be devoted to the consent discussion 
• 
Steps that will be taken to minimize the possibility of coercion or 
undue influence 
• 
Steps that will be taken to ensure the subjects’ understanding 
Response:  
☒ 
We have reviewed and will be following “SOP: Informed Consent Process 
for Research (HRP-090).” 
 
Non-English Speaking Subjects  
☒ 
N/A:  This study will not enroll Non-English speaking subjects.   
(Skip to Section 26.8) 
26.6 Indicate which language(s) other than English are likely to be 
spoken/understood by your prospective study population or their legally 
authorized representatives. 
 
NOTE: The response to this Section should correspond with your response to 
Section 6.4 of this protocol. 
Response:  
26.7 If subjects who do not speak English will be enrolled, describe the process to 
ensure that the oral and written information provided to those subjects will be 
in that language.  Indicate the language that will be used by those obtaining 
consent. 
NOTE:  Guidance is provided on “SOP:  Informed Consent Process for Research 
(HRP-090).” 
Response:  
 
Cognitively Impaired Adults 
☒ 
N/A:  This study will not enroll cognitively impaired adults.   
(Skip to Section 26.9) 
26.8   Describe the process to determine whether an individual is capable of 
consent.  
Response:  
 


 
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Adults Unable to Consent 
☒ 
N/A:  This study will not enroll adults unable to consent.  
(Skip to Section 26.13) 
When a person is not capable of consent due to cognitive impairment, a legally 
authorized representative should be used to provide consent (Sections 26.9 and 
26.10) and, where possible, assent of the individual should also be solicited 
(Sections 26.11 and 26.12). 
26.9  Describe how you will identify a Legally Authorized Representative (LAR).  
Indicate that you have reviewed the “SOP: Legally Authorized 
Representatives, Children, and Guardians (HRP-013)” for research in New 
York State.  
NOTE:  Examples of acceptable response includes: verifying the electronic 
medical record to determine if an LAR is recorded. 
Response:  
☐ 
  
26.10 For research conducted outside of New York State, provide information that 
describes which individuals are authorized under applicable law to consent on 
behalf of a prospective subject to their participation in the research.  One 
method of obtaining this information is to have a legal counsel or authority 
review your protocol along with the definition of “legally authorized 
representative” in “SOP: Legally Authorized Representatives, Children, and 
Guardians (HRP-013).” 
Response:  
26.11 Describe the process for assent of the adults: 
• 
Indicate whether assent will be obtained from all, some, or none of the 
subjects.  If some, indicate which adults will be required to assent and 
which will not. 
Response:  
• 
If assent will not be obtained from some or all subjects, provide an 
explanation of why not. 
Response:  
26.12 Describe whether assent of the adult subjects will be documented and the 
process to document assent.   
NOTE:  The IRB allows the person obtaining assent to document assent on the 
consent document using the “Template Consent Document (HRP-502)” Signature 
Block for Assent of Adults who are Legally Unable to Consent. 
Response:  
 
Subjects who are not yet Adults (Infants, Children, and Teenagers) 


 
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☒ 
N/A:  This study will not enroll subjects who are not yet adults.   
(Skip to Section 27.0) 
26.13 Describe the criteria that will be used to determine whether a prospective 
subject has not attained the legal age for consent to treatments or procedures 
involved in the research under the applicable law of the jurisdiction in which 
the research will be conducted (e.g., individuals under the age of 18 years).  
For research conducted in NYS, review “SOP: Legally Authorized 
Representatives, Children, and Guardians (HRP-013)” to be aware of which 
individuals in the state meet the definition of “children.”  
NOTE:  Examples of acceptable responses include: verification via electronic 
medical record, driver’s license or state-issued ID, screening questionnaire. 
Response:  
26.14For research conducted outside of New York State, provide information that 
describes which persons have not attained the legal age for consent to 
treatments or procedures involved the research, under the applicable law of 
the jurisdiction in which research will be conducted.  One method of obtaining 
this information is to have a legal counsel or authority review your protocol 
along the definition of “children” in “SOP: Legally Authorized 
Representatives, Children, and Guardians (HRP-013).” 
Response:  
26.15 Describe whether parental permission will be obtained from: 
Response: N/A 
☐  One parent even if the other parent is alive, known, competent, reasonably 
available, and shares legal responsibility for the care and custody of the 
child. 
☐ 
Both parents unless one parent is deceased, unknown, incompetent, or not 
reasonably available, or when only one parent has legal responsibility for 
the care and custody of the child. 
☐ 
Parent permission will not be obtained.  A waiver of parent permission is 
being requested. 
NOTE:  The requirement for parent permission is a protocol-specific determination 
made by the IRB based on the risk level of the research.  For guidance, review the 
“CHECKLIST: Children (HRP-416).”  
26.16Describe whether permission will be obtained from individuals other than 
parents, and if so, who will be allowed to provide permission.  Describe your 
procedure for determining an individual’s authority to consent to the child’s 
general medical care. 
Response:  


 
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26.17 Indicate whether assent will be obtained from all, some, or none of the 
children.  If assent will be obtained from some children, indicate which 
children will be required to assent. 
Response:  
26.18 When assent of children is obtained, describe how it will be documented. 
Response:  
27.0 Waiver or Alteration of Consent Process 
Consent will not be obtained, required information will not be disclosed, or the 
research involves deception. 
☒ 
N/A:  A waiver or alteration of consent is not being requested. 
27.1 If the research involves a waiver or alteration of the consent process, please 
review the “CHECKLIST: Waiver or Alteration of Consent Process (HRP-
410)” to ensure that you have provided sufficient information for the IRB to 
make the determination that a waiver or alteration can be granted.   
NOTE:  For records review studies, the first set of criteria on the “CHECKLIST: 
Waiver or Alteration of Consent Process (HRP-410)” applies.  
Response:  
27.2 If the research involves a waiver of the consent process for planned emergency 
research, please review the “CHECKLIST: Waiver of Consent for Emergency 
Research (HRP-419)” to ensure you have provided sufficient information for 
the IRB to make these determinations.  Provide any additional information 
necessary here: 
Response:  
28.0 Process to Document Consent 
☐ 
N/A:  A Waiver of Consent is being requested.   
(Skip to Section 29.0) 
28.1 Indicate whether you will be following “SOP: Written Documentation of 
Consent (HRP-091).” If not or if there are any exceptions, describe whether 
and how consent of the subject will be obtained including whether or not it will 
be documented in writing.   
NOTE:  If your research presents no more than minimal risk of harm to subjects 
and involves no procedures for which written documentation of consent is normally 
required outside of the research context, the IRB will generally waive the 
requirement to obtain written documentation of consent.  This is sometimes 
referred to as ‘verbal consent.’  Review “CHECKLIST: Waiver of Written 
Documentation of Consent (HRP-411)” to ensure that you have provided sufficient 
information.  
If you will document consent in writing, attach a consent document with your 
submission.  You may use “TEMPLATE CONSENT DOCUMENT (HRP-
502)”.  If you will obtain consent, but not document consent in writing, attach the 


 
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script of the information to be provided orally or in writing (i.e. consent script or 
Information Sheet).   
Response:  
☒ 
We will be following “SOP:  Written Documentation of Consent” 
(HRP-091). 
29.0 Multi-Site Research (Multisite/Multicenter Only) 
☒ 
N/A:  This study is not an investigator-initiated multi-site study.  This 
section does not apply. 
 
29.1 If this is a multi-site study where you are the lead investigator, describe the 
processes to ensure communication among sites, such as: 
• 
All sites have the most current version of the IRB documents, including 
the protocol, consent document, and HIPAA authorization. 
• 
All required approvals have been obtained at each site (including 
approval by the site’s IRB of record). 
• 
All modifications have been communicated to sites, and approved 
(including approval by the site’s IRB of record) before the 
modification is implemented. 
• 
All engaged participating sites will safeguard data as required by 
local information security policies. 
• 
All local site investigators conduct the study appropriately. 
• 
All non-compliance with the study protocol or applicable requirements 
will be reported in accordance with local policy. 
Response: 
29.2 Describe the method for communicating to engaged participating sites: 
• 
Problems 
• 
Interim results 
• 
Study closure 
Response:  
29.3 
Indicate the total number of subjects that will be enrolled or records that 
will be reviewed across all sites. 
Response:  
29.4 
If this is a multicenter study for which UB will serve as the IRB of record, 
and subjects will be recruited by methods not under the control of the local site 
(e.g., call centers, national advertisements) describe those methods.  
Response:  
30.0 Banking Data or Specimens for Future Use 


 
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☐ 
N/A:  This study is not banking data or specimens for future use or 
research outside the scope of the present protocol.  This section does not 
apply. 
30.1 If data or specimens will be banked (stored) for future use, that is, use or 
research outside of the scope of the present protocol, describe where the 
data/specimens will be stored, how long they will be stored, how the 
data/specimens will be accessed, and who will have access to the 
data/specimens.  
NOTE:  Your response here must be consistent with your response at the “What 
happens if I say yes, I want to be in this research?” Section of the Template 
Consent Document (HRP-502). 
Response: The study electronic data will be stored in a locked closet and 
password protected computers located in our research locations in Youngs 
Rd and CTRC.  Data is backed up by university on daily bases. Specimens 
will be stored in -80 freezer at our CTRC research laboratory at 875 
Ellicott St. 14203 for at least 7 years. Samples and electronic data will be 
labeled as a coded sample, using the patient randomization number (e.g. 
R12) and visit time and date. Electronic data and specimens will not be 
identifiable. 
The research staff (study personnel including coordinator) only will be 
authorized to access data and or specimens 
30.2 List the data to be stored or associated with each specimen. 
Response: Patient ID number, study visit information and date of collection 
will be stored with specimen.  
30.3 Describe the procedures to release banked data or specimens for future uses, 
including: the process to request a release, approvals required for release, 
who can obtain data or specimens, and the data to be provided with specimens. 
Response: The copy of the individual patient data collected during the study 
period will be provided to these individual patients who can choose to hand 
carry it to their respective physicians and a copy will be faxed to their 
respective clinical providers upon verbal request from the patient. The 
results of the completed study will be made available to the patients if 
requested through published manuscript. Specimens (unidentified) will be 
used by current study staff or future collaboration for other research projects 
with appropriate approvals. 
31.0 Drugs or Devices 
☐ 
N/A:  This study does not involve drugs or devices.  This section does not 
apply. 
31.1 If the research involves drugs or devices, list and describe all drugs and 
devices used in the research, the purpose of their use, and their regulatory 
approval status.  
Response: Drugs used: 


 
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Description or Identity of investigational product(s) 
Investigational 
product 
Dosage form and strength 
Manufacturer 
Exenatide vials  
2.0mg/vial, powder for injection 
AstraZeneca 
Matching Exenatide 
placebo vials  
powder for injection 
AstraZeneca 
- 
Exenatide extended release vials 2.0 mg/vial and matching placebo will be provided 
in one month kits containing: 
• 
One carton containing 4 vials of active or placebo powder  
• 
One carton containing 4 prefilled syringes with diluent, 5 vial adaptors and 8 
needles. 
 
 
31.2 Describe your plans to store, handle, and administer those drugs or devices so 
that they will be used only on subjects and be used only by authorized 
investigators. 
Response: Drugs will be stored in a locked cabinet and temperature controlled 
refrigerator at 4C at the research facility of the Diabetes and Endocrinology 
Center of WNY at 1000 Youngs Rd, Suite 105, Williamsville, NY 14221. The 
study drug will be dispensed and documented by the research nurse, Jeanne 
Hejna. Training on administrating study drug and information about side effects 
and how to report any adverse events will be discussed with patients 
If the drug is investigational (has an IND) or the device has an IDE or a claim 
of abbreviated IDE (non-significant risk device), include the following 
information: 
31.3 Identify the holder of the IND/IDE/Abbreviated IDE. 
Response: IND will not be filed. Exenatide will be used according to indication. 
31.4 Explain procedures followed to comply with FDA sponsor requirements for the 
following:   
 
 
Applicable to: 
FDA Regulation 
IND Studies 
IDE studies 
Abbreviated 
IDE studies 
21 CFR 11 
X 
X 
 
21 CFR 54 
X 
X 
 
21 CFR 210 
X 
 
 
21 CFR 211 
X 
 
 
21 CFR 312 
X 
 
 
21 CFR 812 
 
X 
X 
21 CFR 820 
 
X 
 
Response: All FDA sponsor requirements have been reviewed and will be 
followed during the study procedures 


 
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32.0 Humanitarian Use Devices 
☒ 
N/A:  This study does not involve humanitarian use devices.  This does 
not apply. 
32.1 
For Humanitarian Use Device (HUD) uses provide a description of the 
device, a summary of how you propose to use the device, including a description 
of any screening procedures, the HUD procedure, and any patient follow-up 
visits, tests or procedures. 
Response:  
32.2 
 For HUD uses provide a description of how the patient will be informed 
of the potential risks and benefits of the HUD and any procedures associated with 
its use. 
Response: