LIRAGLUTIDE IN OVERWEIGHT PATIENTS WITH TYPE 1 DIABETES
Phase: PHASE3
Conditions: Type 1 Diabetes
Sponsor: University at Buffalo

 
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 47 
 
 
 
Liraglutide in Overweight Patients with Type 1 Diabetes 
 
NCT number: NCT01753362 
 
Document date: 10/2/2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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IRB Version: JAN2016 
 
 
 
 
 
Complete Research Protocol (HRP-503) 
 
Table of Contents 
Template Instructions.......................................................................................................... 4
1.0
Objectives ................................................................................................................ 6
2.0
Scientific Endpoints ................................................................................................. 7
3.0
Background .............................................................................................................. 8
4.0
Study Design .......................................................................................................... 14
5.0
Local Number of Subjects ..................................................................................... 14
6.0
Inclusion and Exclusion Criteria ............................................................................ 15
7.0
Vulnerable Populations .......................................................................................... 16
8.0
Eligibility Screening .............................................................................................. 18
9.0
Recruitment Methods ............................................................................................. 18
10.0 Procedures Involved ............................................................................................... 19
11.0 Study Timelines ..................................................................................................... 26
12.0 Setting .................................................................................................................... 26
13.0 Community-Based Participatory Research ............................................................ 27
14.0 Resources and Qualifications ................................................................................. 27
15.0 Other Approvals ..................................................................................................... 28
16.0 Provisions to Protect the Privacy Interests of Subjects .......................................... 28
17.0 Data Management and Analysis ............................................................................ 29
18.0 Confidentiality ....................................................................................................... 31
A.
Confidentiality of Study Data ............................................................................ 31
B.
Confidentiality of Study Specimens ................................................................... 31
19.0 Provisions to Monitor the Data to Ensure the Safety of Subjects .......................... 32
20.0 Withdrawal of Subjects .......................................................................................... 34
21.0 Risks to Subjects .................................................................................................... 35
22.0 Potential Benefits to Subjects ................................................................................ 37
23.0 Compensation for Research-Related Injury ........................................................... 37
24.0 Economic Burden to Subjects ................................................................................ 38
25.0 Compensation for Participation ............................................................................. 38
26.0 Consent Process ..................................................................................................... 38
27.0 Waiver or Alteration of Consent Process ............................................................... 43
28.0 Process to Document Consent ............................................................................... 43
29.0 Multi-Site Research (Multisite/Multicenter Only) ................................................. 44
30.0 Banking Data or Specimens for Future Use .......................................................... 44
31.0 Drugs or Devices.................................................................................................... 45
32.0 Humanitarian Use Devices .................................................................................... 46

 
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IRB Version: JAN2016 
 
 
 

 
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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. 
 
 

 
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IRB Version: JAN2016 
PROTOCOL TITLE: 
Include the full protocol title. 
Response: Liraglutide in Overweight Patients with Type 1 Diabetes 
 
PRINCIPAL INVESTIGATOR: 
Name 
Department 
Telephone Number 
Email Address 
Response: Paresh Dandona, M.B.B.S., Ph.D., F.R.C.P, F.A.C.P, F.A.C.C 
Director, Diabetes-Endocrinology Center of Western NY 
           SUNY Distinguished Professor 
Chief of Endocrinology, SUNY at Buffalo 
1000 Youngs Road, Suite 105 
Williamsville NY 14221 
Telephone: (716) 535-1580 
Fax: (716) 639-1200 
E-mail:pdandona@kaleidahealth.org 
Co-Investigators: Husam Ghanim, PhD 
 
 
Antione Makdissi, MD 
 
VERSION: 
Include the version date or number. 
Response: 10/2/2018 
 
 
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: Juvenile Diabetes Research Foundation 
 
 

 
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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 Center of WNY 
Location: 1000 Youngs Road, Suite 105, Williamsville NY 14221 
Address: 1000 Youngs Road, Suite 105, Williamsville NY 14221 
Department: Diabetes Endocrinology & Metabolism  
 
 
 
 
 
1.0 Objectives 
1.1 Describe the purpose, specific aims, or objectives of this research. 
Response: To study the effects of liraglutide (a drug used to treat type 2 
diabetes) on glucose (sugar) control over the 26 week study period when 
used in addition to insulin.  The use of Liraglutide in Type 1 Diabetes is 
investigational 
1.2 Describe the purpose, specific aims, or objectives. 
Response:   
Aim 1.1: To compare the mean HbA1c, fasting glucose, weekly glucose, the standard 
deviation of weekly blood glucose concentrations as recorded by continuous glucose 
monitoring, fructosamine and the dose of insulin required prior to and following 26 weeks 
of treatment with liraglutide. 
Aim 1.2: To compare the postprandial glucose concentrations following a test meal before 
and after 26 weeks of treatment with liraglutide. 
Aim 2.1: To compare the basal and postprandial glucagon and C-peptide concentrations 
following a test meal before and after 26 weeks of treatment with liraglutide. 
Aim 3.1: To compare ROS generation, TBARS, intranuclear NFB binding in MNC, the 
expression of TLR-4,TNFα, IkBα, MMP-9, SOCS-3, PKCβII, PTP-1B, GSK-3β, IKKβ, 
JNK-1, IRβ and pIRβ in MNC and adipose tissue and plasma concentrations of CRP, MCP-
1, PAI-1, TNFα, RANTES, free fatty acids (FFA) prior to and following: a) a single 
injection of liraglutide 1.2mg at first study visit; b) treatment with liraglutide for 26 weeks. 
Aim 3.2: To compare the changes in NFB binding and the expression of TLR-4, TNFα, 
IkBα, SOCS-3, PTP-1B, PKCβII, IKKβ and JNK-1 in MNC following a standard meal 
challenge prior to and after 26 weeks of treatment with liraglutide.. 
Aim 4.1: To assess subcutaneous fat mass, hepatic fat content and visceral fat mass by 
MRI of abdomen and DEXA before and 26 weeks after treatment with liraglutide.  
Aim 4.2: To assess change in waist circumference, blood pressure, triglycerides, HDL 
cholesterol and incidence of metabolic syndrome after treatment with liraglutide 
Aim 5.1: To compare the gastric emptying as measured by acetaminophen absorption 
before and 26 weeks after treatment with daily subcutaneous liraglutide injection. 

 
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Aim 6.1: To compare the blood pressure using a 24 hour blood pressure monitor before 
and 26 weeks after treatment with liraglutide. 
Aim 6.2: To compare endothelial function by measuring flow mediated dilatation (FMD) 
in brachial artery before and 26 weeks after treatment with liraglutide. 
Aim 7.1: To compare the quality of life questionnaire scores and depression 
questionnaire scores before and 26 weeks after treatment with liraglutide 
1.3 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 Liraglutide in overweight or obese patients with 
type 1 diabetes decreases fasting, postprandial and the overall mean glucose 
concentrations while decreasing the dose of insulin required. 
Hypothesis 2: Treatment with Liraglutide decreases basal and postprandial 
glucagon concentrations and increases basal and postprandial C-peptide 
concentrations. 
Hypothesis 3.Treatment with liraglutide suppresses indices of oxidative and 
inflammatory stress including the mediators of insulin resistance, in peripheral 
blood mononuclear cells (MNC), plasma and adipose tissue. 
Hypothesis 4: Treatment with liraglutide reduces abdominal adiposity, hepatic 
and visceral fat mass and improves features of metabolic syndrome. 
Hypothesis 5: Treatment with Liraglutide in obese patients with type 1 diabetes 
delays gastric emptying. 
Hypothesis 6: Treatment with Liraglutide in obese patients with type 1 diabetes 
improves blood pressure and endothelial function. 
Hypothesis 7: Treatment with Liraglutide in obese patients with type 1 diabetes 
improves quality of life and depression as measured by questionnaires. 
 
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: Primary endpoint: Change from baseline in HbA1c at 26 weeks as compared 
to placebo. Secondary endpoints: Change from baseline as compared to placebo in 
a)fasting and postprandial blood sugars, mean weekly glucose concentrations, standard 
deviation of weekly blood sugars and fructosamine; b)fasting and postprandial glucagon 
and C-peptide concentrations; c)insulin doses; d)indices of oxidative and inflammatory 
stress in MNC, plasma and adipose tissue; e)oxidative and inflammatory stress in plasma 

 
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and MNC following meal challenge; f)subcutaneous fat mass, hepatic fat content and 
visceral fat mass; g)waist circumference, blood pressure, triglycerides, HDL cholesterol 
and incidence of metabolic syndrome; h)gastric emptying; i) 24 hour blood pressure; j) 
flow mediated dilatation in brachial artery, k) SF-36 score; l) depression (PHQ) score. 
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: The treatment of type 1 diabetes is based on insulin replacement since the auto-
immune destruction of β-cells leads to a near total loss of endogenous insulin reserve. The 
evolution of therapy in type 1 diabetes since the discovery of insulin in 1921 by Banting 
and Best has largely been based on modifications of insulin preparations or modifications 
of the insulin molecule (insulin analogs) to allow variable bio-availability(1, 2). Different 
ways of delivering insulin and monitoring glucose through subcutaneous insulin infusion 
pumps and continuous glucose monitoring systems have also been devised. Inspite of these 
advances, the control of glucose homeostasis in subjects with type 1 diabetes continues to 
be challenging since exogenous insulin cannot compensate totally for changing 
requirements and is still not precise either in terms of the dose or the bio-availability of the 
insulin injected (3, 4). Furthermore, in the near total absence of endogenous insulin 
secretion, the physiological post prandial inhibition of glucagon secretion by the α-cell is 
probably deficient in all type 1 diabetics, which may also contribute to the variability and 
unpredictability of glucose control with exogenous insulin alone(5). The concomitant use 
of metformin or pramlintide helps in some patients but the results are far from consistent 
and, therefore, these agents have not made an impact on the treatment of this condition(6). 
Thus, there is a need for therapies beyond insulin that can further improve glycemic control 
and reduce fluctuations in glucose in these subjects.  
A recent trial of liraglutide, a glucagon like peptide (GLP)-1 analogue with a 24 hour 
duration of action, in 13 patients with type 1 diabetes led to a remarkable reduction in the 
excursions of blood glucose, both highs and lows, following meals and through the 24 
hours within the first 2 days of treatment in all 13 subjects (7)(see preliminary data section). 
The mean glucose concentrations fell significantly from 136 to 111 mg/dl and the mean 
HbA1c fell significantly from 6.45 to 6.1% in 8 subjects who continued liraglutide for 24 
weeks. The SD of glucose readings fell from 52 to 28. Remarkably, the requirement of 
insulin fell from 51 units to 28 units daily. The treatment also led to a reduction in appetite 
and to weight loss even during the short period of treatment for 9 weeks. The patients felt 
remarkably better and secure in terms of the ‘predictability and stability’ of glycemic and 
appetite control (7). The improvement in glycemia with the reduction in insulin 
requirements within days of starting treatment with liraglutide could be an evidence of 
insulin sensitization and /or endogenous insulinogenesis. Since C-peptide concentrations 
did not alter following the short term administration of liraglutide, it is likely that the 
suppression of glucagon may have contributed to this effect. It is also possible that the 
improvement in glucose homeostasis could partly have been due to a decrease in 
carbohydrate intake and reduced rate of gastric emptying, both of which are known actions 
of GLP-1 analogues (8, 9). 

 
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A recent study has shown that GLP-1 infusion suppresses basal and arginine induced 
glucagon secretion in subjects with type 1 diabetes(10). GLP-1 infusion also completely 
prevents  the rise in post-prandial glucose or glucagon concentrations in these patients(11). 
A study by Rother et al on the effect of exenatide after a meal also showed a trend towards 
a reduction in the increase of glucagon after a meal for the first 45 min although there was 
no significant overall effect(12). In view of the 24 hour duration of action of liraglutide, it 
is possible that it may exert a protracted suppressive effect on glucagon and thus, decrease 
post prandial increases in glucagon concentrations which in turn would reduce post 
prandial excursions of glucose. The importance of glucagon in inducing hyperglycemia is 
further strengthened by the observation that glucagon receptor knockout mice do not 
develop diabetes inspite of complete  cell destruction by streptozotocin(13). Fasting as 
well as postprandial blood sugar concentrations were normal in these animals. 
Our recent observations, mentioned above and described in greater detail below, could 
provide a potentially potent and significant advance in the treatment of type 1 diabetes if 
our investigations demonstrate that the use of liraglutide, a GLP-1 agonist, not only reduces 
glycemia but it reduces the magnitude of excursions of glucose even in stable, well 
controlled type 1 diabetics. This study will be the first randomized controlled prospective 
double blind study investigating the effect of liraglutide in such patients. If this drug is 
shown to be consistently effective, it will provide a major advance in the treatment of 
hyperglycemia and unpredictable alterations in glucose concentrations in type 1 diabetes, 
a disease that is newly diagnosed in 15000 children per year in the US and currently affects 
3 million Americans(14).  
Innovation rationale, and significance 
1. This will be the first prospectively randomized controlled study to investigate the effect 
of liraglutide on glycemic levels and variability in overweight and obese type 1 diabetes 
treated with insulin alone. Liraglutide is the preferred agent for this study since its 
pharmacokinetics and pharmacodynamics ensure a duration of action of 24 hours. 
Hitherto, the treatment of type 1 diabetes is based on insulin replacement with novel 
analogs with appropriate pharmacodynamic profiles or with unique insulin delivery 
systems. The concomitant use of metformin or pramlintide helps in some patients but 
the benefits are far from consistent and, therefore, these agents have not made an impact 
on the treatment of this condition(6). 
2. This will be the first study to investigate the role of glucagon and the potential basal 
and postprandial suppression of glucagon by liraglutide in the pathogenesis and control 
of glycemia in type 1 diabetics. This is particularly important since in the absence of 
insulin secretion from the β–cell, there is no paracrine inhibition of glucagon secretion 
by the α–cell. GLP-1 analogs are known to suppress glucagon(5). 
3. With the use of CGM, this study will determine the rapidity of response by liraglutide, 
which in our preliminary study was observed within the first two days such that we 
advised patients to reduce their insulin doses by 25% in advance. 
4. This will be the first study to attempt to reduce body weight and other features of the 
metabolic syndrome, while improving glycemic control with addition of a single 
therapeutic agent in overweight and obese patients with type 1 diabetes. This is 
particularly relevant since insulin induces weight gain and 40-50% of type 1 diabetics 
in the US have the metabolic syndrome(14). Liraglutide and the only other licensed 
drug in this class, exenatide, have been shown not only to reduce body weight but also 

 
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to reduce systolic blood pressure plasma triglyceride and CRP concentrations in 
subjects with type 2 diabetes(8; 9; 15; 16; 18). 
5. Finally, it will allow us to assess whether liraglutide can activate the dormant β–cells 
which are known to survive in type 1 diabetics for a long time (19). An analysis in a 
subset of the study patients with detectable C-peptide will be carried out separately. 
This will assess the effect of liraglutide in preserving β–cells and the effect of residual 
β-cell function on the action of liraglutide 
 
Liraglutide treatment in patients with type 1 diabetes 
As mentioned above, the treatment of 14 type 1 diabetes patients; age (38.5 years), duration 
of diabetes (204 yrs), weight (666kg), HbA1c% (6.50.5%), C-peptide (< 0.10nmol/l), 
basal insulin dose of 246 units/day, bolus insulin dose of 224 units/day with liraglutide 
in addition to insulin resulted in significant reduction in fasting and mean blood glucose 
concentrations, insulin doses by 45%, HbA1c levels even at 24 weeks, and a reduction in 
appetite and caloric intake with weight loss. In addition, there was a reduction in the 
excursions of blood glucose concentrations, i.e., the standard deviations of blood glucose 
concentrations were markedly reduced. The changes were observed within 48h and 
improved marginally thereafter with fine tuning of insulin doses and a further reduction in 
these doses. The comparison of changes observed early (1 week) vs late (9 weeks) are 
evident in tables 1 and 2.These observations are noteworthy in that they were made in 
patients who had been well controlled, were meticulous, even obsessive, and were on CSII 
and CGM. They had all tried hard to improve their diabetic control by adjusting insulin 
doses but had not succeeded because of the induction of hypoglycemia.  To establish this 
fact, the patients recorded their glucose concentrations for at least two weeks during which 
optimal control was attempted and no significant change was observed (data not shown). 
While our initial plan was to assess the effect with one week treatment, 7 patients wanted 
to continue with Liraglutide and were able to get insurance coverage for this treatment. 
This study was conducted to improve glycemic control in the clinic and not as a randomized 
or placebo controlled trial. In view of the significant effects that were observed (Figure 1), 
we now want to conduct a prospective randomized placebo controlled trial to investigate 
and confirm these effects of Liraglutide in subjects with type 1 diabetes.  
 
Table 1) Effects of Liraglutide after treatment for one week (n=14) 
 
Table 1 
Before treatment 
On Liraglutide P value 
Weight(kg) 
66 ± 6 
65± 5 
0.22 
insulin dose (basal) 
24 ± 6 U/d   
16 ± 6 U/d   
<0.01 
insulin dose (bolus) 
22 ± 4  U/d   
15 ± 4  U/d   
<0.01 
Mean Fasting Blood Glucose (mg/dl) 
129±10 
110±8 
0.02 
Weekly Mean Blood Glucose (mg/dl) 
141±20 
115±12 
<0.01 
Time spent in hypoglycemia <70 mg/dl(% time)  
2.1±2 
2.6±2 
0.08 
Time spent in hypoglycemia  <40 mg/dl(% time)   
0.12±0.2 
0.16±0.3 
0.09 
Time spent in hyperglycemia > 150 mg/dl(% time) 
28± 6 
22± 5 
0.03 
Time spent in hyperglycemia  >200 mg/dl(% time)  
18± 5 
9± 2 
<0.01 
Time spent in hyperglycemia >250 mg/dl(% time) 
8± 2 
1.5± 1 
<0.01 
Mean  weekly SD (mg/dl ) 
56±10 
26±6 
<0.01 

 
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Table 2) Effects of Liraglutide after treatment for mean duration of 24 weeks (n=8) 
 
Figure 1: Weekly continuous glucose monitoring record of one patient prior to and 
following 1 week of liraglutide. Note the glycemic variability (SD) and the frequency of 
glucose concentrations within the target range prior to and following liraglutide 
Fig 1 
 
 
 
 
3.2 Include complete citations or references.  
Table 2 
Before treatment 
On Liraglutide 
P value 
Weight (kg) 
68±5 
64±4 
0.02 
HBA1c % 
6.45±0.5 
6.1±0.4 
0.02 
insulin dose (basal) 
26 ± 7 U/d   
13 ± 6 U/d   
<0.01 
insulin dose (bolus) 
25 ± 4  U/d   
15 ± 4  U/d   
<0.01 
Mean Fasting Blood Glucose (mg/dl) 
125±10 
107±8 
0.02 
Weekly Mean Blood Glucose (mg/dl) 
136±20 
111±12 
<0.01 
Time spent in hypoglycemia <70 mg/dl (% time) 
2±2 
2.4±2 
0.10 
Time spent in hypoglycemia  <40 mg/dl (% time) 
0.1±0.2 
0.14±0.3 
0.21 
Time spent in hyperglycemia > 150 mg/dl(% 
ti
)
27± 6 
20± 5 
0.01 
Time spent in hyperglycemia  >200 mg/dl(% 
ti
)
17± 5 
6± 2 
<0.01 
Time spent in hyperglycemia >250 mg/dl(% 
ti
)
7.5± 2 
1±1 
<0.01 
Mean SD weekly ( mg/dl ) 
52±10 
28±6 
0.01 
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(Lond) 31:285-291, 2007 
27. Louis O, Verlinde S, Thomas M, De Schepper J: Between-centre variability versus 
variability over time in DXA whole body measurements evaluated using a whole body 
phantom. Eur J Radiol 58:431-434, 2006 
28. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, 
Deanfield J, Drexler H, Gerhard-Herman M, Herrington D, Vallance P, Vita J, Vogel 
R: Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated 
vasodilation of the brachial artery: a report of the International Brachial Artery 
Reactivity Task Force. J Am Coll Cardiol 39:257-265, 2002 
29. Perregaux D, Chaudhuri A, Rao S, Airen A, Wilson M, Sung BH, Dandona P: Brachial 
vascular reactivity in blacks. Hypertension 36:866-871, 2000 
30. Garg R, Kumbkarni Y, Aljada A, Mohanty P, Ghanim H, Hamouda W, Dandona P: 
Troglitazone reduces reactive oxygen species generation by leukocytes and lipid 
peroxidation and improves flow-mediated vasodilatation in obese subjects. 
Hypertension 36:430-435, 2000 

 
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31. Perregaux D, Chaudhuri A, Mohanty P, Bukhari L, Wilson MF, Sung BH, Dandona P: 
Effect of gender differences and estrogen replacement therapy on vascular reactivity. 
Metabolism 48:227-232, 1999 
32. Spitzer RL, Kroenke K, Williams JB: Validation and utility of a self-report version of 
PRIME-MD: the PHQ primary care study. Primary Care Evaluation of Mental 
Disorders. Patient Health Questionnaire. JAMA 282:1737-1744, 1999 
33. Sullivan MD, Anderson RT, Aron D, Atkinson HH, Bastien A, Chen GJ, Feeney P, 
Gafni A, Hwang W, Katz LA, Narayan KM, Nwachuku C, O'Connor PJ, Zhang P: 
Health-related quality of life and cost-effectiveness components of the Action to 
Control Cardiovascular Risk in Diabetes (ACCORD) trial: rationale and design. Am J 
Cardiol 99:90i-102i, 2007 
34. Andrews NC, Faller DV: A rapid micropreparation technique for extraction of DNA-
binding proteins from limiting numbers of mammalian cells. Nucleic Acids Res 
19:2499, 1991 
35. Tosi MF, Hamedani A: A rapid, specific assay for superoxide release from phagocytes 
in small volumes of whole blood. Am J Clin Pathol 97:566-573, 1992 
36. Yagi K: Simple assay for the level of total lipid peroxides in serum or plasma. Methods 
Mol Biol 108:101-106, 1998 
 
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 investigation will be a prospective, randomized, double blind, 
placebo controlled parallel design study conducted in patients with type 1 
diabetes. The study will be conducted at Diabetes–Endocrinology Center of 
WNY, affiliated to the State University of New York at Buffalo.  
84 overweight or obese patients with type 1 diabetes on treatment with either 
continuous subcutaneous insulin infusion (CSII; also known as insulin pump) or 
multiple (four or more) injections of insulin per day will be included in the study. 
They will be randomized into 2 groups of 42 patients each. The patients will be 
randomized to daily subcutaneous injections of placebo or liraglutide. In view of 
the possibility of hypoglycemia and the side effect of nausea all patients will be 
started on 0.6 mg of liraglutide per day. The dose will then be titrated up to 1.8 
mg.  
 
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: 84 
5.2 If applicable, indicate how many subjects you expect to screen to reach your 
target sample (i.e. your screen failure rate).  

 
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Response: 100-110. All screened and qualified patients will be enrolled and 
randomized up to 84 enrolled patients. 
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 60 and 100 type 1 diabetic patients every month. 
Therefore, majority of recruited patients are our clinic patients. We do recruit a few 
patients through advertisement 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 
sample.  
NOTE:  This may be done in bullet point fashion. 
Response:  
1) Type 1 Diabetes on continuous subcutaneous insulin infusion (CSII; also known as 
insulin pump) or multiple (four or more) injections of insulin per day. 
2) Using a continuous glucose monitoring device (CGM) or regularly measuring their 
blood sugars four times daily.  
3) HbA1c of less than 10.0%.  
4) Well versed with carbohydrate counting.  
5) Age 18-80 years  
6) BMI≥ 25 kg/m2 
 7) Age at diagnosis of type 1 diabetes should be <30 years.  
8) Evidence of auto-immunity to beta cells (GAD-65 and islet cell antibody screen)  
6.2 Describe the criteria that define who will be excluded from your final study 
sample.   
NOTE:  This may be done in bullet point fashion.  
Response:  1)Type 1 diabetes for less than 6 months;  
2)Coronary event or procedure (myocardial infarction, unstable angina, coronary artery 
bypass, surgery or coronary angioplasty) in the previous four weeks;  
3)Hepatic disease (transaminase > 3 times normal) or cirrhosis;  
4)Renal impairment (serum eGFR <30ml/min/1.73m2);  
5)HIV or Hepatitis B or C positive status;  
6)Participation in any other concurrent clinical trial;  
7)Any other life-threatening, non-cardiac disease;  
8)Use of an investigational agent or therapeutic regimen within 30 days of study. 
 9) history of pancreatitis  
10) pregnancy  
11) inability to give informed consent  
12) history of gastroparesis  

 
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13)history of medullary thyroid carcinoma or MEN 2 syndrome.  
15) Use of any agent other than insulin for treatment of diabetes (metformin, pramlintide 
or thiazolidinediones;  
16) painful gallstones; 
17) alcoholism;  
18) hypertriglyceridemia (>500 mg/dl)  
19) History of pancreatitis 
 
6.3 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:  None of the below populations will be enrolled 
☐ 
Adults unable to consent 
☐ 
Individuals who are not yet adults (infants, children, teenagers) 
☐ 
Pregnant women 
☐ 
Prisoners 
6.4 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.   

 
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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: 
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 

 
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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: :  
Prospective participants will be asked to read and understand the consent and any 
questions they may have regarding the protocol 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. A physical examination will also be done.  
Fasting labs before 10:00am include; CBC, CMP, HbA1c, lipid panel, C-peptide 
and GAD-6 and a urine pregnancy test. Blood samples of patients with negative 
GAD-65 antibodies will be screened for islet cell antibodies, if patient had 
evidence of auto- immunity to beta cells in the past, they will be retested during 
screening. Patients with no evidence of autoimmunity to beta cells will not be 
included in this trial. 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: Participants will be identified by prescreening clinical charts, patient 
doctor interaction at the time of their visits, flyers advertisements 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 

 
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Endocrinology Center of WNY. Patients that may qualify for the study are 
referred to the research team for further eligibility evolution. Patients meeting the 
inclusion and exclusion criteria based on preliminary phone evaluation will be 
invited to participate in the study. 
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. 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; flyer advertisement and researchmatch.org 
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:  
Screening Visit: Consent will be explained and signed. Fasting labs before 10:00am 
include; CBC, CMP, HbA1c, lipid panel, C-peptide and GAD-6 and a urine pregnancy 
test. Physician preformed physical and medical history, including; blood pressure, height 
and weight. Blood samples of patients with negative GAD-65 antibodies will be screened 
for islet cell antibodies, if patient had evidence of auto- immunity to beta cells in the past, 
they will be retested during screening. Patients with no evidence of autoimmunity to beta 
cells will not be included in this trial.   
Study Visit day -14: After screening visit, qualifying patients will see a registered dietitian 
who will review their carbohydrate counting and diet and make an assessment of their 
calorie and carbohydrate intake. Then they will be seen by a CDE for instructions on 

 
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injection technique and CGM insertion. The patients will be blinded to CGM. Patients who 
have been using CGM prior to enrolling in the study can continue to use their CGM’s 
(unblinded). All subjects will be advised to monitor their capillary blood glucose by 
fingerstick before and 2 hours after each meal and to wear their CGM constantly for a 
week. The subjects will also be asked to keep a diary of their food intake for a week to 
measure their calorie intake. Study subjects will not change the type of glucose meter 
during the trial. They will have their body composition measured by DEXA and MRI prior 
to the next visit. Smoking patients will be asked not to change their smoking habits during 
the study. 
Study visit day -7: Meal challenge test: In order to assess the changes induced by 
liraglutide, a meal challenge will be carried out prior to and following liraglutide (week 0 
and week 26): a 910 calorie high fat high carbohydrate meal will be given, as in several of 
our previous papers(20).Bolus dose will be given at 3-4 hours after the ingestion of the 
meal based on the blood sugar and correction factor for each individual subject as giving 
bolus insulin immediately before meal may confound the true effects of liraglutide. 
Acetaminophen (1000 mg for body weight <125lbs, 1250 mg for body weight 125-150 lbs, 
1500 mg for body weight 151-175 lbs and 1750 mg for body weight >175 lbs) will be 
ingested at the beginning of the meal, and the blood levels of acetaminophen will be 
determined at intervals for assessment of the rate of gastric emptying. Liraglutide will be 
injected only at week 26 (45 min prior to the meal). Sequential blood samples will be 
obtained at 0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240 and 300 min. Samples at 15, 30, 
45, 90, 150 and 210 min will be 5 ml while those at 0, 60, 120, 180, 240 and 300 min will 
be 30 ml (total volume=210 ml). Blood will be collected from an indwelling intravenous 
canula in a superficial forearm vein. 
 
Study visit day -1: Subjects will come fasting for this visit. Records of blood glucose 
concentrations monitored by fingerstick and CGM for the previous 14 days will be obtained 
to assess their glycemic control prior to liraglutide treatment (this will serve as the 
baseline assessment of mean blood glucose for the study). The subjects will have their 
24 hour blood pressure measurements completed. Brachial reactivity will be assessed by 
measuring by flow mediated dilation (FMD). They will undergo a meal challenge test 
(described below) and a fat biopsy. 24 hr urine will be collected. 
Study Visit day 0: Subjects will come fasting for this visit. Each subject will be given one 
injection of Liraglutide 1.2 mg or placebo. A fructosamine and blood samples will be 
collected at baseline. Blood samples will be collected after the baseline at 30, 60, 120, 180, 
240 and 300 minutes after the injection. (This is being done to evaluate the acute effect 
of a single injection of Liraglutide on oxidative stress and inflammatory mediators, 
before any adjustments of insulin dose or effect of Liraglutide on blood glucose and 
weight is evident). Subjects will be instructed by the study staff in the dosing and 
administration of the study medication. They will start Liraglutide injection at a dose of 
0.6 mg per day or placebo injection on the following day. We will adjust the doses of basal 
and bolus insulin to eliminate low blood sugars(less than 70 mg/dl). At all subsequent visits 
insulin doses will be titrated to target blood sugars between 70-180 mg/dl at all times. 
Patients will return to the center after 7 days. 
Study Visit week 1: Blood glucose concentrations will be reviewed. Insulin dose will be 
adjusted at the discretion of the study investigator to optimize blood sugar control as per 

 
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the targets mentioned above. Patients will be advised to increase the Liraglutide dose to 
1.2 mg a day if they are able to tolerate the 0.6 mg dose. If they are experiencing mild 
nausea, subjects will continue with 0.6 mg daily for another 7 days. Those with severe 
nausea/vomiting will be dropped from the study. All other subjects will return in 7 days.  
Study Visit week 2: Blood glucose concentrations will be reviewed. Insulin dose will be 
adjusted if needed. Subjects taking 0.6 mg dose and experiencing significant nausea will 
be dropped from the study. Subjects on 1.2 mg and experiencing significant nausea will 
decrease the dose to 0.6 mg and continue that dose for the duration of the study. Subjects 
on 1.2mg and experiencing mild nausea will continue on 1.2 mg for 2 more weeks. Subjects 
on Liraglutide 1.2mg daily without any gastro-intestinal side-effects will be asked to 
increase the dose to 1.8 mg daily. Study drug will be dispensed for additional 2 weeks.  
Study Visit week 4: Subjects will be asked to bring in their used study pens and the pen 
that they are using so that study nurse can log in the amount of drug used. If needed, the 
dose will be increased. The goal in the first 4 weeks is to increase patient’s liraglutide dose 
to maximum tolerated dose. Maximum dose of liraglutide will be 1.8 mg daily. Subjects 
experiencing mild nausea with 0.6 mg or 1.2 mg will continue at that dose in the study. 
Those with severe nausea/vomiting with 1.8mg will decrease their dose to 1.2 mg and 
continue that dose throughout the study. Blood glucose concentrations will be reviewed. 
Insulin dose will be adjusted if needed. CGM will be discontinued. Study drug will be 
dispensed to last till the next visit. 
Study visit week 8: Subjects will be asked to bring in their used study pens and the pen 
that they are using so that study nurse can log in the amount of drug used. Blood glucose 
concentrations will be reviewed. Insulin dose will be adjusted if needed. Study drug will 
be dispensed to last till the next visit. 
Study Visit week 12: Subjects will be asked to bring in their used study pens and the pen 
that they are using so that study nurse can log in the amount of drug used. Blood glucose 
concentrations will be reviewed and vascular activity will be performed. Insulin dose will 
be adjusted if needed. Fasting blood, research labs, HbA1c, fructosamine, lipid panel, urine 
pregnancy test and 24 hr urine will be collected. FMD and 24hr blood pressure will be 
studied. Study drug will be dispensed for additional 4 weeks. 
Study Visit week 16 and 20: Subjects will be asked to bring in their used study pens and 
the pen that they are using so that study nurse can log in the amount of drug used. Blood 
glucose concentrations will be reviewed. Insulin dose will be adjusted if needed. Study 
drug will be dispensed for additional 4 weeks. 
Study visit week 24: CGM will be inserted. They will have their body composition 
measured by DEXA and MRI prior to next visit. 
Study Visit week 26: Subjects will come fasting for this visit. Research labs, CBC, CMP, 
Lipids, HbA1c and fructosamine will be collected. Records of blood glucose 
concentrations monitored by finger-stick and CGM for the previous 14 days will be 
obtained to assess their glycemic control. They will undergo meal challenge test (described 
above) and a fat biopsy. 24 hr urine will be collected. FMD and 24hr blood pressure will 
be performed. After this visit, subjects will be discharged from the study.  
Blood samples (collected in protease and DPP-IV inhibitors) will be appropriately 
processed and assayed for glucose, C-peptide, glucagon, GLP-1 and gastric inhibitory 
peptide (GIP) which is also called gastric insulinotropic peptide, Reactive oxygen species 
(ROS) generation, Thiobarbituric acid reducing substances (TBARS), urinary isoprostane, 

 
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intranuclear nuclear factor kappa B (NFkB) binding, the expression and concentration of 
Toll like receptor-4 (TLR-4), tumor necrosis factor alpha (TNFα), Inhibitor kappa B 
(IkB), Matrix metalloproteinase 9 (MMP-9), Suppressor of cytokine signaling-3 (SOCS-
3), Protein kinase C (PKCII), Phosphotyrosine phosphatase -1B (PTP-1B), Glycogen 
synthase kinase 3 beta (GSK-3), Inhibitor kappa kinase (IKK), C-jun amino terminal 
kinase (JNK-1) and amount of Insulin receptor (IR-) and p-IR in MNC and plasma 
concentrations of C-reactive protein (CRP), Monocyte chemoattractant protein -1 (MCP-
1), Plasminogen activator inhibitor -1 (PAI-1), TNFα and Regulated upon activation 
Normal T cell Expressed and Secreted (RANTES). Adipose tissue samples will be 
processed and analyzed for intranuclear NFkB binding, the expression and concentration 
of TLR-4,TNFα, IkB, MMP-9, SOCS-3, PKCII, PTP-1B, GSK-3, IKK, JNK-1 and 
amount of IR- and p-IR. 
Clinical and Laboratory Procedures  
1.Plasma glucose, glucagon, C-peptide, GLP-1, GIP and FFA measurements: 
Glucose levels will be measured in plasma by YSI 2300 STAT Plus glucose analyzer 
(Yellow Springs, Ohio) (CV 2% for both intra and inter-assay). Free fatty acid levels 
will be measured by a colorimetric assay (Wako, Richmond, VA). CBC and 
comprehensive metabolic panel will be measured using well established assays by the 
clinical laboratory. C-peptide will be measured with Ultrasensitive ELISA kit (LOD 
is 2.5 pg/ml with 3.8% and 5.8% intra and inter-assay CVs) (Mercodia, NC). GLP-1 
(8% and 7% CVs), GIP (2-6% and 3-8% CVs) and glucagon (<5% and <10% CVs) 
will be measured from samples collected in protease and DPP-IV inhibitors by ELISA 
kits form Millipore. 
2.Fat aspiration procedure: Adipocytes will be harvested from the subjects by methods 
previously described in literature (21; 22). Subcutaneous fat tissue aspiration will be 
performed on abdomen at a 10 cm distance from umbilicus. The subjects will not have 
taken aspirin or NSAIDS in the last 72 hours. If that is the case, then the procedure 
will not be done. The skin will first be prepared with povidone-iodine (Betadine) and 
alcohol. A sterile drape will be placed around the appropriate area. 3 cc of 1% 
lidocaine will then be administered subcutaneously. After adequate anesthesia has 
been achieved, approximately 20-50cc of 0.5% lidocaine will be injected in the 
adipose tissue. Dose of lidocaine will not exceed 4.5mg/kg body weight. Aspiration 
of fat tissue will then be performed with a 3-holed canula (Tulip Instrumentation, 
length: 15cm, diameter: 2.1mm) fixed to a 10mL syringe. More than one attempt at 
aspiration can be done at the same site during the procedure to get adequate sample. 
After getting adequate fat tissue (500mg-3g), the puncture site will be pressed for at 
least ten minutes before the patient rises up from supine position (to minimize 
bruising). The study subjects will then be discharged home. The adipose tissue will be 
centrifuged to remove blood and fluid contaminants. The upper adipose tissue will be 
collected into a separate sterile tube, washed twice with cold sterile Phosphate 
Buffered Saline (PBS) and centrifuged to remove the PBS. The adipose tissue sample 
will be weighed and approximately 500 mg transferred to a separate tube for analysis. 
Total RNA, nuclear extracts and total cell lysates will be prepared from the adipose 
tissue. 
3.MRI and DEXA: Multislice MRI of abdomen will be obtained(23). Abdominal 
subcutaneous adipose tissue, hepatic fat and intra-abdominal adipose tissue (adipose 

 
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tissue in the intra-abdominal cavity delineated at the innermost aspect of the 
abdominal and oblique muscle walls surrounding the cavity and the anterior aspect of 
the vertebral body. MRI images will be analyzed in a blinded fashion using customized 
software (24).MRI measurements will be expressed as volume in cm3. All 
measurements will be done at one center, by the same machine and using the same 
software. The coefficient of variation of MRI measured abdominal subcutaneous fat 
is 1-2% and of visceral fat is 3-6%(25; 26). DEXA will used to measure lean body 
mass. Adipose tissue mass will be calculated by subtracting lean body mass from total 
body mass. Adipose tissue mass will be expressed as kilograms. All measurements 
will be done at one center and by the same machine using the same software. The 
within-center variability over time in measurement by DEXA of lean mass is 0.9% 
and of fat mass is 1.2% (27). 
4.24 Hr Blood Pressure monitoring: Ambulo 2400 24-hour Ambulatory Blood Pressure 
Monitoring (ABPM) system from Tiba Medical will be used. 
5. Brachial flow-mediated dilatation (FMD): FMD is the capacity of blood vessels to 
respond to an increase in flow, or more precisely shear stress, by dilating. 
Endothelium-derived nitric oxide is a principal mediator of FMD. A 7.5 – 10 MHz 
broadband multi-frequency linear array transducer will be used to acquire images. The 
subject is positioned supine with the arm in a comfortable position for imaging the 
brachial artery. To create a flow stimulus, a blood pressure cuff is placed on the 
forearm. After acquiring a baseline rest image, arterial occlusion is created by cuff 
inflation to suprasystolic pressure. To occlude arterial inflow for a standardized length 
of time, the cuff is inflated to at least 50 mm Hg above systolic pressure. The resultant 
ischemia triggers dilatation of downstream resistance vessels via autoregulatory 
mechanisms. Following 5 minutes of occlusion, the cuff is deflated. This results in 
reactive hyperemia (a brief high-flow state) in the brachial artery to accommodate the 
dilated resistance vessels. The shear stress that results causes dilatation of the brachial 
artery. The recording of the arterial image is done continuously from 30 seconds 
before to 2 minutes following cuff deflation(28). This procedure has been utilized in 
several studies carried out in our unit, including the first studies describing 
abnormalities in African Americans(29), brachial reactivity improvements related to 
reversal of oxidative stress in the obese and type 2 diabetics following troglitazone(30) 
and gender differences in brachial reactivity and the effect of hormone replacement 
therapy (HRT) in post-menopausal women(31). 
6. Questionnaires: The 36-item short form health survey version 2(SF-36, RAND 
corporation, Santa Monica, CA) will be used to measure quality of life. Depression 
will be assessed by the Patient Health Questionnaire (PHQ) Depression Measure 
(Pfizer Inc, New York, NY).(32; 33) 
7.MNC isolation: Blood samples will be collected in Na-EDTA as an anticoagulant.  
Three and a half mL of anticoagulated blood sample are carefully layered over 3.5 mL 
of PMN medium (Cedarlane Laboratories, Hornby, ON). Samples are centrifuged and 
at the end of the centrifugation, two bands separate out at the top of the RBC pellet. 
The top band consists of MNC, while the bottom consists of PMN. The MNC band is 
harvested and washed twice with Hank's balanced salt solution (HBSS). This method 
provides yields greater than 95% pure PMN and MNC suspensions. 

 
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8.NFB DNA binding activity: Nuclear NFκB DNA binding activity is measured by 
EMSA. Nuclear extract is prepared from MNC and adipose tissue by high salt 
extraction as described by Andrews et al (34). The specificity of the bands is 
confirmed by supershifting these bands with specific antibodies against Rel-A (p65) 
and p50 (Santa Cruz Biotechnology, CA) and by competition with cold 
oligonucleotides. DNA binding activity of NFB will be adjusted to Oct-1 DNA 
binding activity to correct for any variable. 
9.  Plasma concentrations of inflammatory mediators: Concentrations of TNFα (CV: 
5.3% Intra and 8.1% inter-assay, LD: 0.1pg/ml), MMP-9 (CV: 2.2% Intra and 7.1% 
inter-assay, LD: 0.156ng/ml), MCP-1 (CV: 5.7% Intra and 5.2% inter-assay, LD: 
1.7pg/ml) and RANTES (CV: 3.2% Intra and 8.8% inter-assay, LD: 2.0pg/ml) are 
measured in plasma using ELISA kits (R&D Systems, MN). CRP concentrations ( 
CV: 3.5% Intra and 5% inter-assay, LD: 0.35ng/ml) will be measured using an ELISA 
kit from Alpha Diagnostics International Inc. (San Antonio, TX) 
10.  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). Our method (CV intra= <6% and intra= <9%), developed independently 
is similar to that published by Tosi and Hamedani (35).  
11. 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).  
12.  will be measured using the a commercial kit (CVs, intra=6.4% and 
inter= 8.6%) from Zeptometrix (Buffalo, NY) 
13. Quantification of TLR-4, IκBα, TNFα, MMP-9, SOCS-3, PKC-β II, IR-β, PTP-
1B, GSK-3β IKKβ and JNK-1 mRNA, IR and pIR  in MNC by Real-Time 
Reverse Transcription Polymerase Chain Reaction (RT-PCR): Total RNA is 
isolated from MNC and adipose tissue using commercially available RNAqueous®-
4PCR Kit (Ambion, Austin,TX) The quality and quantity of the isolated RNA is 
determined before using the RNA. Real Time RT-PCR is performed using Cepheid 
Smart Cycler (Sunnyvale, CA) in which 2 µL cDNA, 10 µL Sybergreen Master mix 
(Qiagen, CA) along with 0.5 µL of 20 µM gene specific primers (Life Technologies, 
MD) are used. The specificity and the size of the PCR products are tested by adding a 
melt curve at the end of the amplifications and by running it on a 2% agarose gel. All 
values are normalized to 18S expression. 
14. Western blotting of TLR-4, IκBα, IKKβ, IR-β, p-IR-β, JNK-1, SOCS-3, PKC-β 
II, GSK-3β and PTP-1B: MNC and adipose tissue total cell lysates will be prepared 
lysis buffer. Sixty µg of total cell lysate are boiled in SDS buffer and proteins 
separated by SDS-PAGE and then transferred to PVDF membrane. Polyclonal or 
monoclonal antibodies against, TLR-4,IκBα, IKKβ, IR-β, p-IR-β, JNK-1, SOCS-3, 
PKC-β II, GSK-3β and PTP-1B are used and the membranes are developed using 
super signal, chemiluminescence reagent (Pierce Chemical, IL). Densitometry is 
performed using molecular analyst software (Biorad, CA) and all values are corrected 
for loading with actin.  
 
10.2 Describe what data will be collected.   

 
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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 following data will be collected during the conduct of the study 
based on the study design and protocol: HbA1c, fructosamine, average glucose, 
percent time spent in different glycemic thresholds, standard deviations which 
represent the variability in blood glucose, total insulin doses (basal dose, bolus dose 
and total daily dose), changes in carbohydrate intake and helpings; adverse 
events(including the most common side effects of nausea and vomiting which is 
often transient occurring at the time of initiation of liraglutide and at the time of 
escalation of the dose and the rare occurrence of pancreatitis, thyroid c-cell tumors 
and other patient reported adverse events which may occur anytime) and blood 
pressure. The principal investigator Paresh Dandona, MD, PhD and co-
investigators Husam Ghanim, PhD and Antione Makdissi, MD will review the data 
every 3 months to assess the safety of 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 the sponsor (JDRF) and to 
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 patients 
and or in insulin titrations of the study participants will unblind the study groups 
on the discretion of principal investigator and the team will assess potential harm 
to the patients and inform the IRB and sponsor of this potential harm. The corrective 
actions will then be taken and research subjects will be withdrawn from the study 
if risks outweigh the benefits. The IRB will be kept well-informed at all times. 
During each patient visit, evolution of glucose levels (CGM) will be conducted to 
reduce the risk of hypoglycemia or hyperglycemia. After recruitment and 
completion of half of the target number of patients i.e. 42 patients, interim analysis 
will be performed to determine an overwhelming harms or benefits with one 
treatment option compared to another. 
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. Patients 
CGM, dietary intake, BP, weight are monitored every visit to ensure safety. CGM 
graphs will be evaluated every visit. 
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 

 
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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 JDRF and to clinicaltrilas.gov. 
11.0 
Study Timelines 
11.1 Describe the anticipated duration needed to enroll all study subjects. 
Response: 48 months 
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: After the screening visit, subjects who meet the inclusion and 
exclusion criteria, will be assigned a number and randomized to receive 
subcutaneous injection daily of either Liraglutide (42 subjects) or placebo (42 
subjects) for 26 weeks. Total participation period will be 28 weeks including 2 
weeks run in period before starting drug intervention. 
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: 60 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 Road, 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 

 
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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 
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 

 
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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. 
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 who will be available to address any adverse effects or other questions during the 
course of the study 
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. 
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:  
☒ 
N/A:  This study does not require any other approvals. 
16.0 
Provisions to Protect the Privacy Interests of Subjects 
 

 
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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: 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 exclusion criteria and through advertisements. Patient who 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 privately. 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.  
When the patient is being seen at our 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. 
If the patient passes the telephone screening, they will be asked to make an appointment 
to review and sign 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 no 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: The focus of the proposed research is to evaluate the effect of liraglutide on 
mean HbA1c% over the period of 26 weeks of treatment. The similarities between the 
study groups, baseline values for subject’s demographics and study endpoints will be 
compared using appropriate parametric tests. Transformations of the data in order to meet 
statistical assumptions may be considered. The primary endpoint of the study is to detect 

 
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a difference in HbA1c after 26 weeks of treatment with Liraglutide or placebo. The 
statistical analysis will be carried out using analysis of covariance (ANCOVA) and tested 
at the 0.05 level. Change in weight will be a covariate.  The results will be computed as 
mean ± SD. Analysis will be carried out on the basis of intention to treat (with last 
observation carried forward).  
 The secondary end points based on glycemic changes will include the difference from 
baseline in mean weekly glucose concentrations, standard deviations of the mean weekly 
glucose concentrations, HbA1c, fructosamine, the duration of time spent in hyperglycemia 
(>150mg/dl, > 200mg/dl, > 250mg/dl) and hypoglycemia (< 70mg/dl, < 40mg/dl), insulin 
dosage. A reduction in the AUC following the meal will constitute another secondary end 
point. Between groups comparisons of the magnitude of change from baseline will also be 
made for these glycemia related secondary endpoints using student’s t-test. Comparisons 
for these and the primary endpoints will also be made using the paired t-test or Wilcoxson’s 
test for paired data within each group. 
The other secondary end-points of the study will be change from baseline after 26 weeks 
of treatment in the fasting and postprandial blood sugars, glucagon and C-peptide 
concentrations, indices of oxidative and inflammatory stress in MNC, plasma and adipose 
tissue; subcutaneous fat mass, hepatic fat content and visceral fat mass; features of 
metabolic syndrome; gastric emptying, blood pressure, vascular analysis, patient reported 
nausea, quality of life and depression scores. Between groups comparisons will be made 
using students t-test or ANCOVA (adjustment will be done for baseline differences). 
Within group comparisons for these endpoints will be made using paired t-test or 
Wilcoxon’s test or ANCOVA. 
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: There are no prior randomized controlled trials that have examined the 
effect of Liraglutide on HbA1c in subjects with type 1 diabetes. In our observational 
study (preliminary data), we found a decrease in HbA1c of 0.35% after 6 months of 
liraglutide in patients with type 1 diabetes who had a mean HbA1c of 6.45±0.5%. In 
our proposed study, we will include patients with HbA1c up to 8.5%. Thus we expect 
a greater difference in HbA1c among the two groups at the end of the study. 
Conservatively estimating a difference in HbA1c of 0.35% between the two groups, a 
sample size of 32 patients per treatment group should provide 80% power to detect a 
significant difference ( = 0.05), provided the standard deviation of the residuals is 
not greater than 0.5. Thus 64 subjects will be needed for the study. To account for a 
dropout rate of 30%, we will recruit 84 subjects into the study. 
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. 

 
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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 
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 and specimens 
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 specimens and can 
handle transfer of data and samples 
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. Samples that are transported will be done so using dry ice in a 
properly labeled Styrofoam container by the laboratory technician. 
B. Confidentiality of Study Specimens 
 
Describe the local procedures for maintenance of confidentiality of study 
specimens.   

 
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☐ 
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: 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 
18.8 
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 data and 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 data and specimens and can 
handle transfer of data and samples 
18.10 B.  How will the specimens 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. 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 

 
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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 Husam Ghanim, PhD and Antione Makdissi, MD will review the 
data every 3 months to assess the safety of 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 the 
sponsor (JDRF) and to 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 patients and or in insulin titrations of the study participants will 
unblind the study groups on the discretion of principal investigator and the team 
will assess potential harm to the patients and inform the IRB and sponsor of this 
potential harm. The corrective actions will then be taken and research subjects 
will be withdrawn from the study if risks outweigh the benefits. The IRB will be 
kept well-informed at all times. During each patient visit, evolution of glucose 
levels (CGM) will be conducted to reduce the risk of hypoglycemia or 
hyperglycemia. After recruitment and completion of half of the target number of 
patients i.e. 42 patients, interim analysis will be performed to determine an 
overwhelming harms or benefits with one treatment option compared to another. 
19.2 Describe what data are reviewed, including safety data, untoward events, 
and efficacy data. 
Response: Patients CGM, dietary intake, BP, weight are monitored every visit to 
ensure safety. CGM graphs will be evaluated every visit to reduce risk of 
hypoglycemia or hyperglycemia. Other adverse events (including the most 
common side effects of nausea and vomiting, injection site allergic reaction and 
the rare occurrence of pancreatitis, thyroid c-cell tumors and other patient 
reported adverse events) will be collected. 
19.3 Describe any safety endpoints. 
Response: Frequency and severity of hypoglycemia. 
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 
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. 

 
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19.6 Describe who will review the safety data. 
Response: The principal investigator Paresh Dandona, MD, PhD and co-
investigators, Antione Makdissi, 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. 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 the 
sponsor (JDRF) 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 the team will assess potential harm to the 
patients and inform the IRB and sponsor of this potential harm. The corrective 
actions will then be taken and research subjects will be withdrawn from the study 
if risks outweigh the benefits. The IRB will be kept well-informed at all times. 
19.7 Describe the frequency or periodicity of review of cumulative safety data. 
Response: Safety data will be reviewed every 3 months. Study endpoint data will 
be reviewed once after half of the recruited patients have completed the study and 
then at the end of the study 
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 student t-test, Chi-
square and Wilcoxson’s test for paired data 
19.9 Describe any conditions that trigger an immediate suspension of the 
research. 
Response:  
1- New information about the safety of the used drug (Victoza) – liraglutide  
2- Sponsor suspension of the funds. 
3- Significant high incidence of SAE and events leading to withdrawal of 
subjects determined based on the continuous review by the investigators. 
 
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: Pregnancy, DKA, severe and frequent hypoglycemia and drug 
intolerability (severe nausea and/or vomiting) developing any of the exclusionary 
condition listed in the inclusion and exclusion criteria. 

 
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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: 
severe side effect, injury or medical condition which may place the patient at risk 
of further complications if patient continues to participate, failure to take the 
medication as instructed, failure to keep your scheduled appointments, cancellation 
of the study by the sponsor, or other administrative reasons. 
Participation in this research study is voluntary. Subjects have the right to refuse to 
participate or to withdraw from participation at any time for any reason.  Refusal to 
participate or withdrawal from the study will involve no penalty or loss of entitled 
benefits, nor affect the subjects ongoing medical care 
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. 
Response: If a subject withdraws from the research, the data collected to that 
point will be used toward the research finding. Patients are allowed to withdraw 
from some procedures while continuing to participate in the study (take study 
medication). Efficacy and safety data will continue to be collected for the parts of 
study that patients agree to participate in. 
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:   
Subjects who experience severe nausea or vomiting after starting liraglutide will 
discontinue the study. Those with mild or moderate nausea will continue for at 
least one more week. If they continue to experience significant nausea (defined as 
interfering with normal activities), they will discontinue the study. 
Subjects who develop pancreatitis will be withdrawn from the study. 

 
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Subjects who develop a new thyroid tumor during the study will be withdrawn. 
Patients will be informed that they should let study investigators know if they 
develop any swelling in the neck. 
For the entire duration of the study, the patients will maintain a diary to record 
any hypoglycemia and other untoward side effects like nausea, changes in 
appetite and other experiences. 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. They will be specifically asked to call if they have 
hypoglycemia (blood sugar <70 mg/dl) or hyperglycemia (blood sugar >250 
mg/dl) on more than one occasion. The target blood glucose during the study will 
be between 70-180mg/dl at all times, without increasing the incidence of blood 
glucose < 70mg/dl.   
The following Information from the boxed warning in the package insert 
regarding the risk of thyroid c-cell tumors will be discussed in details with all 
participating subjects: 
"Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-
cell tumors at clinically relevant exposures in both genders of rats and mice. It is 
unknown whether Liraglutide causes thyroid C-cell tumors, including medullary 
thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out 
by clinical or nonclinical studies. Liraglutide is contraindicated in patients with a 
personal or family history of MTC and in patients with Multiple Endocrine 
Neoplasia syndrome type 2 (MEN 2). Based on the findings in rodents, 
monitoring with serum calcitonin or thyroid ultrasound was performed during 
clinical trials, but this may have increased the number of unnecessary thyroid 
surgeries. It is unknown whether monitoring with serum calcitonin or thyroid 
ultrasound will mitigate human risk of thyroid C-cell tumors." 
In addition, the following FDA text regarding the risk of developing 
fibrosarcomas will be discussed with all participating subjects 
“In a 2-year repeat subcutaneous dose carcinogenicity study of liraglutide injected 
once a day in CD-1 mice, a treatment-related increase in fibrosarcomas was seen 
on the dorsal skin and subcutis, the body surface used for drug injection, in males 
in the 3 mg/kg/day group. These fibrosarcomas were attributed to the high local 
concentration of drug near the injection site. The liraglutide concentration in the 
clinical formulation (6 mg/mL) is 10 times higher than the concentration in the 
formulation used to administer 3 mg/kg/day liraglutide to mice in the 
carcinogenicity study (0.6 mg/mL)”. 
21.2 Describe procedures performed to lessen the probability or magnitude of 
risks, including procedures being performed to monitor subjects for safety. 
Response: For the entire duration of the study, the patients will maintain a diary to 
record any hypoglycemia and other untoward side effects like nausea, changes in 
appetite and other experiences. 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. They will be specifically asked to call if they have hypoglycemia 

 
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(blood sugar <70 mg/dl) or hyperglycemia (blood sugar >250 mg/dl) on more than 
one occasion. Insulin doses will be titrated to target blood sugars between 70-180 
mg/dl at all times without increasing the incidence of blood glucose < 70mg/dl. 
The following Information from the boxed warning in the package insert regarding 
the risk of thyroid c-cell tumors will be discussed in details with all participating 
subjects. 
21.3 If applicable, indicate which procedures may have risks to the subjects that 
are currently unforeseeable. 
Response: Any adverse effects of Liraglutide that are not currently known or 
those unique to their use in Type 1 diabetes 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: There are no potential benefits individual participants will experience 
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.   
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. 

 
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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: No contract injury language available. 
 
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:  
700.00 after completion of all study visits and procedures:- 
 $50 for study visit day 1, 
 $50 for each fat biopsy, 
 $50 for each meal challenge, 
 $50 for each 24 hour blood pressure monitoring 
 $25 for blood draw (week 12) 
 $15 for each urine sample  
 $15 per visit (for visits 1, 2, 4, 8, 16, 20 and 24) 
 $15 for each DEXA scan 
 $25 for each MRI 
 $15 for each brachial reactivity study 
☐ 
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.   

 
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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, 
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 

 
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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:  
 
 
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). 

 
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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:  
☐ 
We have reviewed and will be following “SOP: Legally Authorized 
Representatives, Children, and Guardians (HRP-013).”  
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) 
☒ 
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 

 
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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:  
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. 

 
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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 
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). 

 
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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 
☐ 
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 

 
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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. Other data stored will include record files of all patients 
participating in the study, including data collection sheets, lab results, CGM and 
insulin pump data. 
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 data 
provided will include the insulin pump or CGM data or any of the lab results 
obtained during the study period. The results of the completed study will be 
made available to the patients if requested through published manuscript. 
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:  
Investigational 
product 
Dosage form 
and strength 
Approval status 
Manufacturer 

 
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Liraglutide 1.2mg-
1.8mg 
Pen Injection 
Approved for type 2 
diabetes 
Novo Nordisk 
Matching placebo for 
Liraglutide 1.2 mg-
1.8mg 
Pen Injection 
N/A 
Novo Nordisk 
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. 
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 holder: Dr Paresh Dandona. FDA has issued IND exempt and this 
is on file with IRB 
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. 
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:  

 
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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: