A Double-Blind, Placebo-Controlled Trial of Anti-Aging, Pro-Autophagy Effects of Metformin in Adults With Prediabetes
Phase: PHASE3
Conditions: PreDiabetes, Aging
Sponsor: University of New Mexico

PROTOCOL TITLE: A Double-Blind, Placebo-Controlled Trial of Anti-Aging, Pro-
Autophagy Effects of Metformin in Adults with Prediabetes
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Version Date: May 8,2018
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PROTOCOL TITLE: A Double-Blind, Placebo-Controlled Trial of Anti-Aging, Pro-
Autophagy Effects of Metformin in Adults with Prediabetes
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PROTOCOL TITLE:  A Double-Blind, Placebo-Controlled Trial of Anti-Aging, Pro-Autophagy 
Effects of Metformin in Adults with Prediabetes
PRINCIPAL INVESTIGATORS: Mark Burge, M.D. Division of Medicine/Endocrinology
Vojo Deretic,Ph.D., Department of Molecular Genetics & Microbiology
VERSION NUMBER:
Version 2
DATE:
May 08,2018
REGULATORY FRAMEWORK:
Please indicate all that apply:
DOD (Department of Defense)
DOE (Department of Energy)
DOJ (Department of Justice)
ED (Department of Education)
EPA (Environmental Protection Agency)
FDA (Food and Drug Administration)
HHS (Department of Health and Human Services)
VA
Other: CTSC Pilot Study
Is this a clinical trial under ICH-GCP E6?   
 Yes   
 No
If yes, please confirm that the research team is familiar with and agrees to comply with 
the investigator requirements cited in ICH-GCP E6.  
 Yes   
 No 
ICH-GCP E6 can be accessed by copying and pasting this URL into your browser: 
http://www.fda.gov/downloads/Drugs/Guidances/ucm073122.pdf

PROTOCOL TITLE: A Double-Blind, Placebo-Controlled Trial of Anti-Aging, Pro-
Autophagy Effects of Metformin in Adults with Prediabetes
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Table of Contents
1.
Objectives...................................................................................................................4
2.
Background ................................................................................................................4
3.
Study Design ..............................................................................................................6
4.
Inclusion and Exclusion Criteria ...............................................................................10
5.
Number of Subjects..................................................................................................11
6.
Study Timelines........................................................................................................12
7.
Study Endpoints .......................................................................................................12
8.
Research Setting......................................................................................................12
9.
Resources Available.................................................................................................14
10.
Prior Approvals .....................................................................................................15
11.
Multi-Site Research ..............................................................................................15
12.
Study Procedures .................................................................................................16
13.
Data Analysis........................................................................................................18
14.
Provisions to Monitor the Data to Ensure the Safety of Subjects .........................19
15.
Withdrawal of Subjects .........................................................................................20
16.
Data Management/Confidentiality.........................................................................20
17.
Data and Specimen Banking ................................................................................22
18.
Risks to Subjects ..................................................................................................23
19.
Potential Benefits to Subjects ...............................................................................24
20.
Recruitment Methods............................................................................................25
21.
Provisions to Protect the Privacy Interests of Subjects ........................................25
22.
Economic Burden to Subjects...............................................................................26
23.
Compensation.......................................................................................................27
24.
Compensation for Research-Related Injury..........................................................27
25.
Consent Process ..................................................................................................27
26.
Documentation of Consent ...................................................................................31
27.
Study Test Results/Incidental Findings.................................................................31
28.
Sharing Study Progress or Results with Subjects ................................................32
29.
Inclusion of Vulnerable Populations......................................................................32
30.
Community-Based Participatory Research...........................................................33
31.
Research Involving American Indian/Native Populations .....................................34
32.
Transnational Research........................................................................................34
33.
Drugs or Devices ..................................................................................................35
Checklist Section .............................................................................................................35

PROTOCOL TITLE: A Double-Blind, Placebo-Controlled Trial of Anti-Aging, Pro-
Autophagy Effects of Metformin in Adults with Prediabetes
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1.1. Objectives: Describe the purpose, specific aims, or objectives.
This proposal is for a Phase III study to examine the beneficial, pro-autophagy effects of 
Metformin in adults with prediabetes.  
Our long term goal is to develop a phase III study in response to a specific NIH FOA using high 
content screening of leucocyte LC3 puncta scores, qRT-PCR transcription factor EB (TFEB) 
scores, and assays of total DNA methylation and galectin-3, to gauge the magnitude of 
metformin’s effects on autophagy and cell senescence as markers of aging in adults with 
prediabetes. This study will provide preliminary data for such a proposal and will also fill a 
knowledge gap regarding the use of validated biomarkers in this field.  It will also contribute 
significantly to the overall anti-aging literature. The primary objective of this proposal is to 
validate the autophagy experimental design in humans by using leucocyte LC3, TFEB, Galectin-
3, and total methylation of DNA scores as markers of autophagy activity and cell senescence.
1.2. State the hypotheses to be tested.
AIM 1: Demonstrate that metformin therapy will increase cellular autophagy as an 
inverse correlate of aging as measured by increases in LC3 and TFEB scores. 
Hypothesis 1: In addition to beneficial effects on glycemia, body weight, and body 
composition, metformin therapy exerts beneficial effects on surrogate measures of 
autophagy and aging.
Primary outcome: Increased levels of LC3 in leukocytes.
AIM 2: Demonstrate that metformin therapy will mitigate evidence of aging as 
measured by increased DNA methylation and decreased serum galectin 3 among 
adults with prediabetes. 
Hypothesis 2: Metformin therapy exerts beneficial effects on DNA methylation as measures 
of aging
Primary outcome: Increased DNA methylation in leukocytes.
AIM 3: Monitor the beneficial metabolic effects of metformin in adults with 
prediabetes. Hypothesis 3: Metformin therapy will elicit the expected beneficial effects on 
glycemia, body weight, insulin resistance, and body composition demonstrated in previous 
studies.
Primary outcome: Decreased A1c. 
2.
Background
2.1. Describe the relevant prior experience and gaps in current knowledge.
Anti-aging medicine is a burgeoning field, and accumulating data implicates the cellular 
process of autophagy as the primary mechanism of normal aging and the diseases 
associated with aging. Autophagy is considered to be a process of “cellular recycling” and is 
known to affect a spectrum of health and disease states associated with aging, including 
inflammatory disorders, metabolic syndrome and type II diabetes, cardiovascular disease, 
cancer and neurodegeneration. The dynamics of autophagy are strictly controlled by 
autophagy-related genes as well as by one of the central regulators of metabolism AMPK, 
the target of metformin. Autophagy also affects stem cells and cellular senescence. When 
the process of autophagy fails, the result is a state of chronic inflammation and degenerative 
diseases in many systems.

PROTOCOL TITLE: A Double-Blind, Placebo-Controlled Trial of Anti-Aging, Pro-
Autophagy Effects of Metformin in Adults with Prediabetes
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2.2. Describe any relevant preliminary data.
Diabetes can be considered a disease of premature aging, and many of the salutary effects 
of metformin therapy in diabetes can be interpreted as slowing or reversing the aging 
process. For example, in Western societies, 44% of patients with type 2 diabetes die within 
10 years of diagnosis [1], and the incidence of, and mortality from, cardiovascular disease 
are 2–3 times greater in patients with diabetes than in the general population [2]. In current 
practice, metformin is the consensus first-line therapy for type 2 diabetes not only for its 
potent anti-hyperglycemic effects, but also for its well-documented improvements in 
endothelial dysfunction, hemostasis, oxidative stress, insulin resistance, lipid profiles, and 
fat redistribution [3]. Metformin may also decrease adverse cardiovascular outcomes 
independent from its glucose-lowering activity, and it likely has anti-proliferative effects in 
cancer and may also exert a neuroprotective effect [4]. These apparent pleiotropic effects of 
metformin make it a prime candidate for investigation as an anti-aging therapy.
What is Autophagy? Autophagy is a key feature of aging cells and a ubiquitous process of 
cellular senescence in human tissues. It can be described as an irreversible arrest in cellular 
proliferation. Autophagy is a key cellular homeostatic [5,6] and metabolic process [7-12] that 
is the center of a rapidly evolving area of biomedical research with broad fundamental and 
medical significance [13-28]. Autophagy responds to growth factors and is also exquisitely 
sensitive to cellular energy and nutritional status (e.g.- amino acids, glucose, ATP, NAD+, 
Acetyl-CoA, and neutral lipid stores) through very specific regulatory systems [29-38]. 
Autophagy affects a spectrum of human health and disease states [13, 17, 21-28], including 
inflammatory and autoimmune disorders [19,21,39,40], metabolic conditions such as obesity 
and diabetes [11,12,41-43], cardiovascular problems [17,25] cancer [13,15,20,28,44,45] 
neurodegeneration [18,22,40,46], infectious processes [21], and age-related diseases [47-
49]. 
Autophagy and Metabolism: Autophagy enables regulation of glucose metabolism, and its 
failure contributes to the Metabolic Syndrome, insulin resistance, and diabetes [12,41,42,60-
63]. Drugs such as metformin may affect autophagy [64]. Additionally, autophagy has 
connections with adipogenesis and lipolysis [11], and the cardinal regulators of metabolism 
in mammalian cells are also key upstream regulators of autophagy [9-11].
Autophagy and Inflammation: Autophagy directly and indirectly governs (often suppressing) 
activation of major inflammatory pathways associated with the pathogenesis of many 
diseases [17,19,39,50-54, 66]. It also modulates other global inflammatory processes, such 
as interferon responses [39]. These responses are key to maintaining normal immune 
homeostasis: failure of autophagy can lead to chronic inflammatory conditions (i.e.- Crohn’s 
Disease [57,66-70], cancer [23,28], infections (tuberculosis [21,58, 59, 71,72] or HIV and 
other viruses [73-76]), and autoimmunity [56,77-82]. 
Synergy Between Autophagy, Inflammation, and Metabolism: Autophagy and metabolic 
abnormalities such as obesity, diabetes, atherosclerosis, and inflammation are interrelated 
[83-86]. For example, cholesterol crystals [87], fatty acids [88, 89], obesity-linked lipotoxicity 
of ceramide [89], and amylin [91] are known inflammasome agonists and inducers of 
inflammation.  Autophagy suppresses inflammasome activation [17,19,21,39, 50-55]. 
Autophagy also modulates lipid metabolism [9-11].

PROTOCOL TITLE: A Double-Blind, Placebo-Controlled Trial of Anti-Aging, Pro-
Autophagy Effects of Metformin in Adults with Prediabetes
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All of this is relevant for aging. Rapamycin’s effects on aging have been observed for years 
[92-117], and Metformin’s impact on aging implicates similar mechanisms, but with improved 
metabolic sequelae [93,118].
2.3. Provide the scientific or scholarly background for, rationale for, and significance of the 
research based on the existing literature and how will it add to existing knowledge.
Numerous studies have documented the benefits conferred by the glucose-lowering agent 
Metformin. In animal models, Metformin is shown to increase both lifespan and healthspan, 
and a clinical trial (NCT02432287) is currently ongoing to determine whether this effect 
translates to humans, as well as how the medication alters the adult human transcriptome. 
In vitro studies demonstrate Metformin’s ability to mitigate aging- and disease-related 
inflammation, oxidative damage, and diminished autophagy. Additionally, there are 
numerous cohort, case-control and meta-analysis studies confirming metformin’s reduction 
in cancer-related death via hypothesized activity in the relevant mTOR, HER2, miRNA and 
TGF-alpha 
pathways. 
As 
such, 
NIH 
has 
issued 
FOA 
PA-17-073 
(https://grants.nih.gov/grants/guide/pa-files/PA-17-073.html) to solicit additional clinical 
studies that will evaluate Metformin’s effects on aging and age-related conditions. 
3.
Study Design
3.1. Describe the study design 
(e.g., observational; 
randomized placebo-
controlled clinical trial, etc.)
We will perform a randomized, 
quasi-double blind, placebo-
controlled trial of metformin in 
adult patients with prediabetes.  
Inclusion criteria will comprise 
individuals aged 30-70 years 
(inclusive) with prediabetes 
(defined as an A1c of 5.7-6.4%) 
and a BMI between 27 and 40 
kg/m2 (inclusive).  Exclusion 
criteria will include prior 
treatment with metformin or 
other diabetes medications, 
pregnancy, the presence of 
significant renal dysfunction 
(Serum Creatinine > 1.3 mg/dl 
for women, > 1.4 mg/dl for 
men), severe hepatic 
dysfunction (AST or ALT > 3 
times the upper limit of normal), 
ongoing alcohol or substance 
abuse, inflammatory bowel 
disease, ongoing glucocorticoid 
therapy, or inability to render 
informed consent.
Figure 1: Anti-Aging, Pro-Autophagy Effects of Metformin in Adults with Prediabetes 
Study Description: A phase III study to examine the beneficial pro-autophagy effects of metformin in 
adults with prediabetes.  We hypothesize that in addition to beneficial effects on glycemia, body weight, 
and body composition, metformin therapy exerts beneficial effects on surrogate measures of inflammation 
and aging, as measured by two separate autophagy measures, in adult patients with prediabetes. 
V1 - 50 adults aged 30-70 years at risk for diabetes are screened with a 
physical exam, a health history questionnaire and an A1c. 
Lifestyle Modification 
(ADA Diet + 10,000 Steps Per Day)
+
Metformin 500 mg po BID titrated to 1000 q AM 
and 500 q PM over one month, as tolerated.
Random, 
Semi-Blinded
Lifestyle Modification 
(ADA Diet + 10,000 Steps Per Day)
+
Placebo (CaCO3) 648 mg po BID titrated to 1296 q 
AM and 648 q PM over one month, as tolerated.
V2 - Collect Baseline Data: Primary Outcomes: A1c, Leucocyte LC3 Score, & DNA Methylation. 
Secondary Outcomes: Cr, BMI, Body Composition, fasting glucose, HOMA-IR, TFEB, and galectin-3
V3 - Collect 4 Week Data: Primary Outcomes: A1c, Leucocyte LC3 Score, & DNA Methylation. 
Secondary Outcomes: Cr, BMI, Body Composition, fasting glucose, HOMA-IR, TFEB, galectin-3, and step 
counts.
4 Weeks
30 individuals with prediabetes aged 30-70 are enrolled.  Exclusion Criteria: Inflammatory bowel 
disease, glucocorticoid or diabetes drug therapy, GFR < 60 cc/min. 
V4 - Collect 12 Week Data: Primary Outcomes: A1c, Leucocyte LC3 Score, & DNA Methylation. 
Secondary Outcomes: Cr, BMI, Body Composition, fasting glucose, HOMA-IR, TFEB, galectin-3, and step 
counts.
8 Weeks

PROTOCOL TITLE: A Double-Blind, Placebo-Controlled Trial of Anti-Aging, Pro-
Autophagy Effects of Metformin in Adults with Prediabetes
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As summarized in the accompanying Figure 1, all subjects will complete four study–related 
visits. All visits will occur within a 7-day window of the target date. At Visit 1, informed 
consent will be obtained, a brief medical history and physical examination will be performed, 
and a health-history questionnaire will be completed by the participant. Blood samples will 
also be obtained for eligibility criteria at this visit.  Women of child-bearing age will receive a 
urine pregnancy test at Visit 1. 
At Visit 2, randomization to placebo or active Metformin will occur.  All subjects will receive 
standardized instruction about diet and exercise for the prevention of diabetes and will be 
provided with a pedometer. Participants will subsequently be instructed to attempt to walk at 
least 10,000 steps per day five days during each week for the 12-week duration of the study. 
A step diary will be provided for subjects to complete daily to collect their step data.
As shown in Table 1, 
the following data will 
be collected at visit 
two (Week 0), visit 
three (4 weeks), and 
visit four (12 weeks).  
After randomization, 
all subjects will 
receive 90 days 
worth of study 
medication in the 
form of either 
Metformin or Placebo 
(i.e.- nearly identical 
Calcium carbonate 
[CaCO3]) as prepared and labelled by the UNM Hospital research pharmacist, Susan 
Kunkel, PharmD. Subjects will start on doses of Metformin 500 mg po BID, and then the 
dose will be titrated up to 1000 mg po q AM and 500 mg po q PM over the course of 1 
month, as tolerated. Subjects assigned to receive CaCO3 will receive 648 mg po BID, and 
then the dose will be titrated up to 1296 mg po q AM and 648 mg po q PM over the course 
of 1 month, as tolerated. 
Study investigators will be blinded to treatment assignment, and the study randomization list 
will be maintained by Dr. Kunkel. It should be noted that because Metformin has a distinctive 
odor, it is not possible to fully blind this study. For the purposes of this pilot study, however, 
we will take advantage of the fact that the dosages and appearance of CaCO3 tablets and 
metformin tablets are very similar, and because study investigators and data collectors will 
be blinded to treatment, we believe that the study design is adequately robust. 
FDA Regulatory Considerations: Metformin has an excellent long-term safety record and is 
already FDA approved for utilization in prediabetes. As such, attainment of an FDA IND is not 
necessary for this study. CaCO3 is being administered in a manner consistent with current 
guidelines: 1000 mg of elemental calcium are recommended per day for adults, and our dosage 
delivers 780 mg of elemental calcium daily 
(https://medlineplus.gov/magazine/issues/winter11/articles/winter11pg12.html).
Table 1: Study Visit Summary
Visit Number
Data Obtained
Blood 
Volume
1
(Screening)
Blood: A1c, Lytes, BUN, Cr, Fasting Glucose, AST, ALT.  Urine Pregnancy.
Anthropomorphics: Height, Weight
Other: Health History, Physical Exam, AUDIT Questionnaire
22 ml
2
(Week 0, 
Baseline)
Blood: A1c, Fasting BMP, Insulin, LC3, TFEB, Galectin-3, DNA Methylation.
Anthropomorphics: Height, Weight, Body Composition by BIA.
Other: Health History, Physical Exam, Distribute Step Diary.
60 ml
3
(Week 4)
Blood: A1c, Fasting BMP, Insulin, LC3, TFEB, Galectin-3, DNA Methylation.
Anthropomorphics: Height, Weight.
Other: Health History, Physical Exam, Step Diary, Pill Counts.
60 ml
4
(Week 12)
Blood: A1c, Fasting BMP, Insulin, LC3, TFEB, Galectin-3, DNA Methylation.
Anthropomorphics: Height, Weight, Body Composition by BIA.
Other: Health History, Physical Exam, Step Diary, Pill Counts.
60 ml

PROTOCOL TITLE: A Double-Blind, Placebo-Controlled Trial of Anti-Aging, Pro-
Autophagy Effects of Metformin in Adults with Prediabetes
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Lifestyle Intervention: All study participants will be educated in the importance of lifestyle 
modification in a manner consistent with the Diabetes Prevention Program [122], and all 
subjects will be expected to follow these instructions throughout the course of the 12 week 
study period. Specifically, subjects will be asked to attempt to achieve a modest reduction in 
total calories (500-1000 kcal/d) each day [123], as is consistent with the recommendations 
of the American Diabetes Association [124]. We will also ask participants to approach the 
physical activity recommendations of the Diabetes Prevention Program by asking them to 
walk 10,000 steps per day at least five days per week [125]. This amount of exercise will 
approximate the 150 minutes of moderately strenuous exercise achieved by participants in 
the lifestyle intervention arm of the Diabetes Prevention Program.  
Study Population:  
We will recruit 
potential subjects 
with prediabetes 
from the 
Endocrinology 
Clinics, from the 
CTSC participant 
recruitment service, 
and from the UNM 
Prediabetes Cohort 
Registry. This latter 
registry is the result 
of a small CDC-
sponsored study 
performed at UNM 
a few years ago 
that identified 104 
subjects with prediabetes out of 218 at-risk subjects who were screened (HRRC # 11-422) 
[126]. These subjects agreed to be contacted in the event of future research involving 
prediabetes. We will also employ CTSC-sponsored social media to recruit for this study, if 
necessary. We do not anticipate much difficulty identifying subjects who are interested in 
participating in this study. We estimate that 50 adults at risk for diabetes will need to be 
screened to find 30 eligible subjects with prediabetes to enroll in this study.
Data Analysis: For continuous variables (i.e.- A1c, Body Mass Index, HOMA-IR index, Body 
Composition, LC3 Score, TFEB Score, Total DNA Methylation, and Galectin-3 
concentrations), we will analyze the change from baseline (Week 0) at Week 12 using a two-
tailed unpaired t-test.  Repeated Measures Analysis of Variance will also be performed 
using the 0, 4, and 12 week data with study drug as the grouping factor and study variable 
as the repeated factor. We will assume a moderate correlation of 0.7 for laboratory values 
obtained within subjects over time, and we will again compare responses in the subjects 
who received metformin with those who received placebo. Descriptive statistics comparing 
baseline characteristics of the study participants will employ the two-tailed unpaired t-test for 
continuous variables, or the Chi-Square or Fisher Exact test for frequency data, as 
appropriate.
Table 2: Study Outcome Measures
Study Variable
What It Measures
Metformin Effect
Aim 1: LC3
This test quantitates intracellular autophagosome formation; a 
marker of autophagy.
Increase
TFEB
This test quantitates via qRT-PCR, changes in gene 
expression levels of TFEB-regulated genes.  
Increase
Aim 2: Total 
DNA 
Methylation
This test quantitates the amount of methylated DNA in a 60 ng 
sample of isolated DNA from PBMCs relative to a methylated 
control sample.
Increase
Galectin-3
A regulatory molecule acting at various stages along the 
continuum from acute to chronic inflammation and 
fibrogenesis.
Increase
Aim 3: A1c
Average glucose concentration over 90 days.
Decrease
BMI
Body mass normalized to height.
Decrease
HOMA-IR Index
Insulin sensitivity using fasting glucose & insulin.
Decrease

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Autophagy Effects of Metformin in Adults with Prediabetes
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Sample Size Determination and Power:  Primary outcome variables for this study are 
“increase in LC3 Score from baseline” for Aim 1, “increase in total DNA methylation” for Aim 
2, and “decrease in A1c” from baseline” for Aim 3. Secondary outcome variables (not 
powered) are TFEB score for Aim 1, Galectin-3 concentrations for Aim 2, and BMI and 
HOMA-IR index (using fasting glucose and insulin) for Aim 3. These outcome variables are 
summarized in Table 2.  We will enroll 30 subjects into this study and assume a dropout rate 
of 20%, leaving 12 subjects per group for data analysis. Sensitivity analysis will also be 
performed with an “intention to treat” analysis using the last value carried forward for 
subjects who dropped out.  
For Aim 1, with 12 subjects per group, a difference in change in LC3 Score from baseline of 
8±4 Dots Per Cell (DPC) for Metformin vs. 3±4 DPC for Placebo can be detected in PBMCs 
using a two-tailed, unpaired t-test with α = 0.05 and β = 0.83. Baseline LC3 score is 
assumed to be 2±2 DPC and not different between groups. This hypothesized difference is 
typical of those observed in Dr. Deretic’s previous in vitro studies.
LC3 is our primary outcome variable for Aim 1. During the process of autophagy, 
autophagosomes engulf cytoplasmic components and concomitantly, the cytosolic form of 
LC3 (LC3-I) is conjugated to phosphatidyl ethanolamine, resulting in the autophagosomal 
membrane-bound form (LC3-II). LC3-II is a widely used marker to monitor autophagosome 
formation by quantitation of the number of LC3-labeled puncta (autophagosomes, or “dots”) 
per cell detected by fluorescence microscopy.  An increase in LC3 puncta formation denotes 
an increase in autophagic activity. The Deretic Lab has employed this technique in many 
different cell types, including human monocyte-derived macrophage cells (MDMs). Here, 
MDMs from human subject donors will be cultured and adhered in full media in 96 well 
plates and then immunostained to detect endogenous LC3 using Anti-LC3 polyclonal 
antibody (MBL P036) and a secondary fluorescent antibody. Plates will then be imaged 
using a Cellomics HCS scanner. This device will automatically capture cell images while 
identifying and quantifying LC3 puncta according to pre-set parameters in the HCS Studio 
software. This approach eliminates the problems of user subjectivity inherent in conventional 
microscopy studies while generating sufficient data from many hundreds of cells for robust 
and reproducible studies.
For Aim 2, we will employ the Imprint Methylated DNA Quantification Kit (Sigma-Aldrich, St. 
Louis, MO). This kit quantitates the amount of methylated DNA in a 60 ng sample of isolated 
DNA from PBMCs relative to a methylated control sample. Gomes and colleagues described 
a study comparing the total DNA methylation of young (26.5 years) and older (70.8 years) 
healthy subjects. They found a pattern of relative DNA hypo-methylation among the older 
subjects: 18.2±1.6% in the older subjects versus 21.9±3.0% in the younger subjects [127]. 
With 12 subjects per group, we can detect a difference of this magnitude with α = 0.05 and β 
= 0.82.  
For Aim 3, with 12 subjects per group, a difference in change in A1c from baseline of 
0.7±0.4% for Metformin vs. 0.2±0.4% for Placebo can be detected with using a two-tailed 
unpaired t-test with α = 0.05 and β = 0.83. Baseline A1c is assumed to be 6.1±0.4% and not 
different between groups.
Potential Challenges:  If adherence to lifestyle modification is significantly different between 
groups, this could become an important confounder. If this occurs, we will perform a 

PROTOCOL TITLE: A Double-Blind, Placebo-Controlled Trial of Anti-Aging, Pro-
Autophagy Effects of Metformin in Adults with Prediabetes
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Repeated Measures ANCOVA using “steps per day” and “change in body mass” as 
covariates.
3.2. Describe blinding, if applicable
Study investigators will be blinded as to study assignment of those 30 individuals enrolled, 
and the study randomization list will be maintained by UNM Hospital Research Pharmacist 
Susan Kunkel, Pharm.D.  Randomization list will be devised and maintained by Dr. Kunkel.
4.
Inclusion and Exclusion Criteria
4.1. Describe how individuals will be screened for eligibility.
Screening will occur at the UNM CTSC Clinical Research Unit.
Inclusion criteria will comprise individuals aged 30-70 years (inclusive) with prediabetes 
(defined as an A1c of 5.7-6.4%) and a BMI between 27 and 40 kg/m2 (inclusive).
Exclusion criteria will include prior treatment with metformin or other diabetes medications, 
pregnancy, the presence of significant renal dysfunction (Serum Creatinine > 1.3 mg/dl for 
women, > 1.4 mg/dl for men), severe hepatic dysfunction (AST or ALT > 3 times the upper 
limit of normal), ongoing alcohol or substance abuse, inflammatory bowel disease, ongoing 
glucocorticoid therapy, or inability to render informed consent.
 
4.2. Describe the criteria that define who will be included or excluded in your final study 
sample.
Inclusion criteria will comprise individuals aged 30-70 years (inclusive) with prediabetes 
(defined as an A1c of 5.7-6.4%) and a BMI between 27 and 40 kg/m2 (inclusive).
Exclusion criteria will include prior treatment with metformin or other diabetes medications, 
pregnancy, the presence of significant renal dysfunction (Serum Creatinine > 1.3 mg/dl for 
women, > 1.4 mg/dl for men), severe hepatic dysfunction (AST or ALT > 3 times the upper 
limit of normal), ongoing alcohol or substance abuse, inflammatory bowel disease, ongoing 
glucocorticoid therapy, or inability to render informed consent.
During the screening assessments, we will employ the AUDIT questionnaire to determine 
whether the participant’s behaviors constitute alcohol abuse.  The AUDIT questionnaire 
(attached) has been added to the “Supporting Documents” section of the proposal.  A score 
of 13 or more in a female, or 15 or more in a male, will constitute an exclusionary criterion 
for the study.
For the purposes of excluding other drugs of abuse, we will simply ask the participant the 
following question: “Have you used heroin, cocaine, or methamphetamine, or misused other 
narcotic drugs, over the past 30 days?”  A yes response will constitute an exclusionary 
criterion for the study.
For women of child-bearing age, exclusion criteria include current pregnancy. Further, they 
must agree to not get pregnant during this study and to use an effective method of birth 
control during the course of the study.  
4.3. Indicate specifically whether you will include each of the following special populations: 
(You may not include members of the above populations as subjects in your research 
unless you indicate this in your inclusion criteria.)

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Autophagy Effects of Metformin in Adults with Prediabetes
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
Adults unable to consent

Individuals who are not yet adults (infants, children, teenagers)

Pregnant women

Prisoners
We will not include adults unable to consent, individuals who are not yet adults, pregnant 
women or prisoners in this study.
4.4. Indicate if you excluding any particular populations (e.g., women, children, persons not 
fluent in English, a particular racial or ethnic group, etc.) and provide justification. 
For the purposes of this study we will recruit only adults.  No gender, racial or ethnic groups will 
be excluded.  No Spanish language consent form is currently being prepared, but we will 
consider adding this if there is sufficient demand.
5.
Number of Subjects
5.1. If this is a multicenter study, indicate the total number of subjects to be accrued across 
all sites.
This study will be conducted at only one site, the University of New Mexico Health Sciences 
Center, Albuquerque, New Mexico.  
5.2. Indicate the number of subjects to be recruited at this site.  
We estimate that 50 adults at risk for diabetes will need to be screened to find 30 eligible 
subjects with prediabetes to enroll in this study.
5.3. Provide sample size justification
For Aim 1, with 12 subjects per group, a difference in change in LC3 Score from baseline of 
8±4 Dots Per Cell (DPC) for Metformin vs. 3±4 DPC for Placebo can be detected in PBMCs 
using a two-tailed, unpaired t-test with α = 0.05 and β = 0.83. Baseline LC3 score is 
assumed to be 2±2 DPC and not different between groups. This hypothesized difference is 
typical of those observed in Dr. Deretic’s previous in vitro studies.
LC3 is our primary outcome variable for Aim 1. During the process of autophagy, 
autophagosomes engulf cytoplasmic components and concomitantly, the cytosolic form of 
LC3 (LC3-I) is conjugated to phosphatidyl ethanolamine, resulting in the autophagosomal 
membrane-bound form (LC3-II). LC3-II is a widely used marker to monitor autophagosome 
formation by quantitation of the number of LC3-labeled puncta (autophagosomes, or “dots”) 
per cell detected by fluorescence microscopy.  An increase in LC3 puncta formation denotes 
an increase in autophagic activity. The Deretic Lab has employed this technique in many 
different cell types, including human monocyte-derived macrophage cells (MDMs). Here, 
MDMs from human subject donors will be cultured and adhered in full media in 96 well 
plates and then immunostained to detect endogenous LC3 using Anti-LC3 polyclonal 
antibody (MBL P036) and a secondary fluorescent antibody. Plates will then be imaged 
using a Cellomics HCS scanner. This device will automatically capture cell images while 
identifying and quantifying LC3 puncta according to pre-set parameters in the HCS Studio 
software. This approach eliminates the problems of user subjectivity inherent in conventional 
microscopy studies while generating sufficient data from many hundreds of cells for robust 
and reproducible studies.

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For Aim 2, we will employ the Imprint Methylated DNA Quantification Kit (Sigma-Aldrich, St. 
Louis, MO). This kit quantitates the amount of methylated DNA in a 60 ng sample of isolated 
DNA from PBMCs relative to a methylated control sample. Gomes and colleagues described 
a study comparing the total DNA methylation of young (26.5 years) and older (70.8 years) 
healthy subjects. They found a pattern of relative DNA hypo-methylation among the older 
subjects: 18.2±1.6% in the older subjects versus 21.9±3.0% in the younger subjects [127]. 
With 12 subjects per group, we can detect a difference of this magnitude with α = 0.05 and β 
= 0.82.  
For Aim 3, with 12 subjects per group, a difference in change in A1c from baseline of 
0.7±0.4% for Metformin vs. 0.2±0.4% for Placebo can be detected with using a two-tailed 
unpaired t-test with α = 0.05 and β = 0.83. Baseline A1c is assumed to be 6.1±0.4% and not 
different between groups.
6.
Study Timelines
6.1. Describe:

The duration of an individual subject’s participation in the research

The duration anticipated to enroll all subjects

The expected duration for the investigators to complete the study (complete analysis)
Participation in this study by research subjects will take a total of approximately 6-10 hours over 
a period of 12 weeks, and 4 visits to the UNM HSC Clinical Research Unit will be required 
(including the initial screening visit).  Total time to complete sample processing and analysis is 
estimated to be approximately 3 months subsequent to the end of data collection.  The entire 
study, from the beginning of funding and enrollment to the end of the funding cycle is estimated 
to be one year.
           
7.
Study Endpoints
7.1. Describe the primary and secondary study endpoints.
AIM 1: Demonstrate that Metformin therapy will increase cellular autophagy as an 
inverse correlate of aging as measured by increases in LC3 and TFEB scores. 
Hypothesis 1: In addition to beneficial effects on glycemia, body weight, and body 
composition, Metformin therapy exerts beneficial effects on surrogate measures of 
autophagy and aging.
Primary outcome: Increased levels of LC3 in leukocytes.
AIM 2: Demonstrate that Metformin therapy will mitigate evidence of aging as 
measured by increased DNA methylation and decreased serum Galectin 3 among 
adults with prediabetes. 
Hypothesis 2: Metformin therapy exerts beneficial effects on DNA methylation as measures 
of aging
Primary outcome: Increased DNA methylation in leukocytes.
AIM 3: Monitor the beneficial metabolic effects of Metformin in adults with 
prediabetes. Hypothesis 3: Metformin therapy will elicit the expected beneficial effects on 
glycemia, body weight, insulin resistance, and body composition demonstrated in previous 
studies.

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Primary outcome: Decreased A1c. 
7.2. Describe any primary or secondary safety endpoints.
TFEB, scores, Galectin-3 levels, BMI, HOMA-IR, fasting glucose, step-counts, pill-counts, 
body composition, serum creatinine, history and physical exam.
7.3. Describe any exploratory endpoints.
None.
8.
Research Setting
8.1. Describe the sites or locations where your research team will conduct the research.
Recruitment, screenings, health questionnaires, subject measurements and phlebotomy will 
be conducted at the CTSC Clinical Research Unit.  
Cell purification and culturing from blood will be conducted at the CTSC T1 laboratory, while 
LC3 cell treatment and analysis will be conducted in the laboratories of Dr. Vojo Deretic, in 
the Department of Molecular Genetics and Microbiology, Fitz Hall, Rooms 355, 357 and 
371.
8.2. Identify where your research team will identify and recruit potential subjects.
We will recruit potential subjects with prediabetes from the Endocrinology Clinics, from the 
CTSC participant recruitment service, and from the UNM Prediabetes Cohort Registry 
(HRRC # 11-422). These latter subjects agreed to be contacted in the event of future 
research involving prediabetes. We will also employ CTSC-sponsored social media to recruit 
for this study, if necessary. We do not anticipate having difficulty identifying subjects who 
are interested in participating in this study. We estimate that 50 adults at risk for diabetes will 
need to be screened to find 30 eligible subjects with prediabetes to enroll in this study.
8.3. Identify where research procedures will be performed including any laboratory analytics
Study subject interviews, body measurements and phlebotomy will be conducted at the 
CTSC Clinical Research Unit.
Measurements of A1c, creatinine, fasting blood glucose, electrolytes, and insulin will be 
conducted in the CTSC Clinical Research Unit using the CTSC Clinical Laboratory or 
Tricore Laboratory. 
Cell purification and culturing from subject’s blood draw will be conducted utilizing 
dedicated bench space in the CTSC T1 laboratory.  Cell purification will carry along no 
personal identifiers, only the blinded numeric assignment, and utilize Ficoll gradient 
separation for isolation of the mononuclear layer.  The services of the T1 Lab will also be 
used for subsequent RNA purifications, cDNA production, qRT-PCR, DNA Methylation 
measurements, and assay quantifications.  
Cultured cells labeled with the blinded numeric assigned will be transferred to the 
laboratories of Dr. Vojo Deretic, in Fitz Hall for cell treatment and analysis. Cells 
undergoing autophagy can be identified by visualizing fluorescently-labeled LC3 puncta 
and/or the co-localization of fluorescently labeled LC3 and lysosomal markers.  LC3 
measurements will be quantified using our Cellomics ArrayScan® VTI HCS Reader with a 
fully automated microscope featuring Zeiss optics for HTS high-content screening of 96 

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well plates utilizing iDev Intelligent Assay Development workflow software essential for high 
content analyses studies by trained personnel.  
The expression of 4 autophagy genes known to be regulated by TFEB and a control will be 
measured and analyzed via qRT-PCR.
8.4. Describe the composition and involvement of any community advisory board
A community advisory board will not be utilized.
8.5. For research conducted outside of UNM HSC and its affiliates describe:

Site-specific regulations or customs affecting the research

Local scientific and ethical review structure/requirements (Note: include any 
approvals (IRB, facility, or other) with your submission)
There will be no research conducted outside of UNM HSC and its affiliates.
9.
Resources Available
9.1. Describe the qualifications of the PI and study staff (e.g., training, experience, 
oversight) as required to perform the research. When applicable describe their 
knowledge of the local study sites, culture, and society. 
Mark Burge, M.D., A faculty Endocrinologist who is widely experienced in the 
performance of clinical trials.
Vojo Deretic, Ph.D., Chair of Molecular Genetics and Microbiology and a world authority 
on autophagy. 
Lindsey VanDyke, D.O., Endocrinology Fellow in Training.
9.2. When applicable, describe which licensed physicians/providers will be responsible for 
medical decision-making and ordering and evaluation of necessary diagnostics and 
therapeutics. 
Mark Burge, MD, and Lindsey VanDyke, DO, are licensed physicians who will assume 
responsibility for medical decision making in this study.
9.3. Describe other resources available to conduct the research: For example, as 
appropriate:

Justify the feasibility of recruiting the required number of suitable subjects within the 
agreed recruitment period. For example, how many potential subjects do you have 
access to? What percentage of those potential subjects do you need to recruit?

Describe the time that will be devoted to conducting and completing the research.

Describe the facilities available to conduct the research.

Describe the availability of medical or psychological resources that subjects might 
need as a result of an anticipated consequences of the human research.

Describe the process to ensure that all persons assisting with the research are 
adequately informed about the protocol, the research procedures, and their duties 
and functions.
We will recruit potential subjects with prediabetes from the Endocrinology Clinics, from 
the CTSC participant recruitment service, and from the UNM Prediabetes Cohort 

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Registry. This latter registry is the result of a small CDC-sponsored study performed at 
UNM a few years ago that identified 104 subjects with prediabetes out of 218 at-risk 
subjects who were screened (HRRC # 11-422). 
These subjects agreed to be contacted in the event of future research involving 
prediabetes. We will also employ CTSC-sponsored social media to recruit for this study, 
if necessary. We do not anticipate having difficulty identifying subjects who are 
interested in participating in this study. We estimate that 50 adults at risk for diabetes 
will need to be screened to find 30 eligible subjects with prediabetes to enroll in this 
study.
As this is a Pilot Study, our timeline, is to recruit subjects, conduct the research and 
collect data, and analyze the data within a one year time frame.
LC3 measurements will be quantified using our Cellomics ArrayScan® VTI HCS 
Reader with a fully automated microscope featuring Zeiss optics for HTS high-content 
screening of 96 well plates utilizing iDev Intelligent Assay Development workflow 
software essential for high content analyses studies by trained personnel in the Deretic 
Lab, located in Fitz Hall, Room 355. Other instrumentation utilized is located in the 
CTSC T1 laboratories.
The UNM CTSC will supply study coordinator services for this study.

If CTSC resources are being accessed, the signed CTSC resources attachment 
must be uploaded on the CTSC Submission page in Click.
A signed CTSC Resources Attachment has been uploaded on the CTSC submission 
page in Click.
10. Prior Approvals
10.1. Describe any approvals that will be obtained prior to commencing the research. (e.g., 
school, external site. funding agency, laboratory, radiation safety, or biosafety 
approval.)
None.
10.2. Upload the required Departmental Review Form signed by your Department Chair (or 
authorized designee if the PI is the Department Chair) into Click under “supporting 
documents.”
Done.
10.3. If a study includes ionizing radiation, the Radiation Safety Attachment (HUS-FORM_1) 
must be uploaded (attached) in Click with your submission.  The consent should 
include radiation exposure information in the Risks section.
Not applicable.
10.4. If applicable to the study, include the signed “Biological Specimens” and/or “Drug 
Attachment” in Click with your submission.

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Done.
11. Multi-Site Research   
  
Not applicable.
11.1. If this is a multi-site study where the UNM HSC PI is the lead investigator, or UNM 
HSC is the coordinating site, describe the processes to ensure communication among 
sites, such as:

All sites have the most current version of 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 will conduct the study appropriately.

All non-compliance with the study protocol or applicable requirements will reported in 
accordance with local policy.
11.2. Describe the method for communicating to engaged participating sites:

Adverse events

Problems

Interim results

Data and safety monitoring reports

The closure of a study
11.3. If the UNM HSC investigator is serving as the “sponsor-investigator” of a FDA-
regulated trial, describe how sponsor responsibilities will be fulfilled, including, but not 
limited to:

Trial Monitoring

Investigational Product Accountability

Safety and other interim reporting to investigators and FDA

Unanticipated Problem reporting to investigators, IRBs, and FDA
12. Study Procedures 
12.1. Describe, in chronological order, all research procedures and interventions being 
performed and when they are performed. Include:

Each specific intervention, procedure, examination, imaging, laboratory test, etc. that 
subjects will undergo for the purposes of the research and the purpose of it.
At the initial screening visit, subjects will receive a standard medical history and 
physical examination, and medical records and current medication lists will be 
reviewed by study personnel. They will be asked to complete a short health-history 
questionnaire. If female of child-bearing age, they will receive a urine pregnancy test to 
ensure that they are not pregnant. They will be asked to submit to a small blood draw 

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to determine A1c and test that kidney and liver function are normal. It is expected that 
this visit will take 1 or 2 hours to complete.
After enrollment, at Baseline Week 0 visit, Week 4 and Week 12 visits, subjects will 
have the following measured, including a draw of 12 teaspoons of blood:

Medical history and physical exam, health history questionnaire.

Body composition (percent lean, percent fat), by Bioelectrical Impedance.

Height, weight and blood pressure.

A1c level (a measure of blood sugar over the past several weeks)

Fasting blood glucose

Fasting serum Insulin

Electrolytes

Serum Creatinine

LC3 score (measured via cultured mononuclear cells and LC3 antibody)

TFEB score (measured via cultured mononuclear cells and qRT-PCR) 

Galectin-3 score (measured via assay) 

DNA Methylation (measured via Imprint Methylated DNA Quantification Kit 
(Sigma-Aldrich, St. Louis, MO).

Step diary (measured via pedometer step counts)

Count of remaining pills of study medication remaining  
No specific genetic tests will be performed during this study.

Each drug, biologic, device, or other such product used in the research, the purpose, 
and the regulatory status (e.g., investigational, marketed – on label, marketed – off 
label, etc.)
Randomized, double-blind assignment to –
Metformin 500 mg po BID, and then the dose titrated up to 1000 mg po q AM and 500 po 
q PM over the course of 1 month, or…
CaCO3 Placebo, 648 mg po BID, and then the dose titrated up to 1296 mg po q AM and 
648 po q PM over the course of 1 month.

Each survey, questionnaire, interview, focus group, etc., that subjects will be asked 
to complete or participate in for the research and the purpose of it.
Health History Questionnaire has been uploaded.
Step Diary has been uploaded.
Each data source that will be used to gather information about subjects and the purpose 
of it (confidentiality will be addressed later.

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For UNM patients, participant electronic medical records may be reviewed for 
inclusion and exclusion criteria, concomitant medical conditions, and medication list.

Indicate whether subjects would already be expected to undergo any of the 
procedures for clinical, diagnostic, or other non-research purposes
None.

Include all referenced study instruments, such as questionnaires, scripts, diaries, and 
data collection forms with your submission as separate attachments.
Uploaded.

For HUDs, provide a description of the device, a summary of how you propose to 
use the device, including any screening procedures, the HUD procedure, and any 
patient follow-up visits, tests, or procedures.  Note whether the HUD is being used 
for clinical purposes only or if you are proposing to study the safety or effectiveness 
of the device.
Bioelectrical Impedance will be used to determine body composition.  This device is 
well validated, safe, and is being used for study data purposes.
Visit
Screening:
1-2 hour outpatient visit
Week 0;
1-2 hour outpatient visit
Week 4 (± 7 days):
1-2 hour outpatient visit
Week 12 (± 7 days):
2 hour outpatient visit
Event
Sign consent form. Medical 
history and physical exam, 
health history 
questionnaire. Labs for 
A1c, blood salts, kidney 
and liver function. Urine 
pregnancy test (if 
appropriate)
Height and weight, body 
composition. Labs for A1c, 
blood sugar, insulin, fasting 
glucose, blood salts, kidney 
function, TFEB, LC3 score, 
Galectin 3 and DNA 
Methylation.  Study medication 
& step-counter provided
Height and weight. 
Labs for A1c, fasting 
glucose, insulin, blood 
salts, kidney function, 
TFEB, LC3 score, 
Galectin 3 and DNA 
Methylation.  Study 
medication and step-
diary collected.
Height and weight, body 
composition. Labs for 
A1c, fasting glucose, 
insulin, blood salts, 
kidney function, TFEB, 
LC3 score, Galectin 3 
and DNA Methylation.  
Study medication and 
step-diary collected
13. Data Analysis
13.1. Describe the data analysis plan, including any statistical procedures.
13.2. Provide a power analysis
For Aim 1, with 12 subjects per group, a difference in change in LC3 Score from baseline of 
8±4 Dots Per Cell (DPC) for Metformin vs. 3±4 DPC for Placebo can be detected in PBMCs 
using a two-tailed, unpaired t-test with α = 0.05 and β = 0.83. Baseline LC3 score is 
assumed to be 2±2 DPC and not different between groups. This hypothesized difference is 
typical of those observed in Dr. Deretic’s previous in vitro studies.
LC3 is our primary outcome variable for Aim 1. During the process of autophagy, 
autophagosomes engulf cytoplasmic components and concomitantly, the cytosolic form of 
LC3 (LC3-I) is conjugated to phosphatidyl ethanolamine, resulting in the autophagosomal 
membrane-bound form (LC3-II). LC3-II is a widely used marker to monitor autophagosome 
formation by quantitation of the number of LC3-labeled puncta (autophagosomes, or “dots”) 
per cell detected by fluorescence microscopy.  An increase in LC3 puncta formation denotes 

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an increase in autophagic activity. The Deretic Lab has employed this technique in many 
different cell types, including human monocyte-derived macrophage cells (MDMs). Here, 
MDMs from human subject donors will be cultured and adhered in full media in 96 well 
plates and then immunostained to detect endogenous LC3 using Anti-LC3 polyclonal 
antibody (MBL P036) and a secondary fluorescent antibody. Plates will then be imaged 
using a Cellomics HCS scanner. This device will automatically capture cell images while 
identifying and quantifying LC3 puncta according to pre-set parameters in the HCS Studio 
software. This approach eliminates the problems of user subjectivity inherent in conventional 
microscopy studies while generating sufficient data from many hundreds of cells for robust 
and reproducible studies.
For Aim 2, we will employ the Imprint Methylated DNA Quantification Kit (Sigma-Aldrich, St. 
Louis, MO). This kit quantitates the amount of methylated DNA in a 60 ng sample of isolated 
DNA from PBMCs relative to a methylated control sample. Gomes and colleagues described 
a study comparing the total DNA methylation of young (26.5 years) and older (70.8 years) 
healthy subjects. They found a pattern of relative DNA hypo-methylation among the older 
subjects: 18.2±1.6% in the older subjects versus 21.9±3.0% in the younger subjects [127]. 
With 12 subjects per group, we can detect a difference of this magnitude with α = 0.05 and β 
= 0.82.  
For Aim 3, with 12 subjects per group, a difference in change in A1c from baseline of 
0.7±0.4% for Metformin vs. 0.2±0.4% for Placebo can be detected with using a two-tailed 
unpaired t-test with α = 0.05 and β = 0.83. Baseline A1c is assumed to be 6.1±0.4% and not 
different between groups.
Potential Challenges:  If adherence to lifestyle modification is significantly different between 
groups, this could become an important confounder. If this occurs, we will perform a 
Repeated Measures ANCOVA using “steps per day” and “change in body mass” as 
covariates.
14. Provisions to Monitor the Data to Ensure the Safety of Subjects
This section is required when research involves more than Minimal Risk to subjects. Describe:
14.1. The entity (e.g., DMC, DSMB) or individuals (e.g., medical monitor) who will perform 
data and safety monitoring.  Describe whether they are independent of or affiliated with 
the sponsor or investigator.  If a DMC or DSMB is planned, describe the composition 
of the committee or board. Generally, a DSMB or DMC should be composed of experts 
in all scientific disciplines needed to analyze and interpret the data (e.g., 
epidemiologists, biostatisticians, subject matter experts).
We will employ Dr. David Schade, MD, to act as an independent monitor in the 
capacity of our Data Safety and Monitoring Board. Dr. Schade is independent of this 
study and has no vested interest in its outcome.  Treatment for diabetes in this study is 
consistent with current standard of care, and the risks of Metformin or CaCO3 therapy 
are generally mild and well characterized. We will track all study-related adverse 
events and prepare a report for Dr. Schade’s review each year prior to protocol 
renewal for the HRRC.  We will track patients who are unable to tolerate study 
medication for any reason, including gastrointestinal complaints.  We will also track 
and report all SAEs, as is standard for all clinical trials. 

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14.2. The safety information that will be collected and monitored.
Serum creatinine.
14.3. The frequency or periodicity of review of data, such as specified points in time or after 
a specific number of participants have been enrolled.
Safety and efficacy data will be collected at 0, 4 and 12 weeks. DSM reports will be 
prepared for the DSMB annually at the time of HRRC protocol renewal.
14.4. The plans for review of scientific literature and data from other sources that may inform 
the safety or conduct of the study.
Literature review was performed by Lindsey VanDyke, DO, and Michal Mudd from Dr. 
Deretic’s lab.
14.5. The procedures for analysis and interpretation of the safety data.
Adverse event rates will be compared following conclusion of the study.
14.6. The conditions that would trigger a suspension or termination of the research (i.e., 
stopping rules), if appropriate.
An unexpected high rate of SAEs (40% or greater) would prompt unblinding and 
investigation to see if these events are clustered in one group or another.  If that is the 
case, the DSMB and the IRB would be consulted to see if cessation of the study is 
warranted.  
14.7. The plan for reporting findings to the sponsor, investigators, and HRRC.
AE reporting will be to the HRRC as is standard for clinical trials.
15. Withdrawal of Subjects
15.1. Describe any anticipated circumstances under which subjects may be withdrawn from 
the research without their consent.
Subjects may be withdrawn from the study for any reason. These typically include 
cessation of communication with the research team.
15.2. Describe any procedures for orderly termination/safe withdrawal (e.g., tapering of 
meds, physical exams, laboratory or other tests, etc.).
No tapering of medication is necessary with CaCO3 or Metformin.  Study drug will be 
discontinued at the end of the study or upon subject withdrawal. If desired by the 
participant, we will communicate with the participant’s primary care physician about 
study treatment, study drug assignment, and results at the conclusion of the study.
15.3. Describe any procedures for partial withdrawal (e.g., from procedures but allowing 
continued data collection by record review, phone contact, etc.).
We will attempt to schedule a study close-out visit for any participant who is withdrawn 
from the study. Failing that, we will attempt to conduct an exit interview via telephone.
15.4. Describe the disposition of existing data/specimens when a subject withdraws.  
Describe any restrictions on a subject’s ability to withdraw any already gathered data 
or specimens (e.g., unable to retrieve because it has been stripped of identifiers and 

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no code exists to allow re-linking).  (Note: FDA requires that existing data be 
maintained for studies subject to FDA oversight.).
Study data will be maintained for up to 10 years after completion of the study. 
Thereafter, identified study data will remain available in the Lobo Vault as per NIH 
data-sharing regulations.  
15.5. Describe withdrawal procedures and any limitations in the consent document.
Participants are informed of their right to withdraw in the consent form.
16. Data Management/Confidentiality
16.1. Indicate how the research team is permitted to access any sources of information 
about the subjects.
Subjects will agree to allow study staff to access and review their UNM electronic 
medical records.  No disclosure will be made outside of study staff.  No PHI will be 
divulged in resultant publications of this research.
16.2. Note whether the research requires the access, use, or disclosure of direct identifiers 
(e.g., name, medical record number, etc.)
We will maintain patient identifiers in a separate file maintained on a secure UNM 
computer and in Dr. Burge’s folder on the H drive.
16.3. Note whether the research requires the access, use, or disclosure of Protected Health 
Information.
Subjects will agree to allow study staff to access and review their UNM electronic 
medical records.  No disclosure will be made outside of study staff.  No PHI will be 
divulged in resultant publications of this research.
16.4. Note whether the data includes information that may be considered sensitive or require 
additional protections such as HIV, genetic test results, mental health information, 
substance abuse information, criminal records, etc. 
Not applicable.
16.5. Indicate whether a Certificate of Confidentiality will be used to protect data from 
forced release (e.g., subpoena) and whether the certificate is in place or will be 
applied for once IRB approval is in place.  More information on Certificates of 
Confidentiality is available here: http://grants.nih.gov/grants/policy/coc/index.htm 
Not applicable.
16.6. Describe the steps that will be taken secure the data (e.g., training, authorization of 
access, password protection, encryption, physical controls, certificates of 
confidentiality, and separation of identifiers and data) during storage, use, transmission 
and transport.
Subjects will be assigned Unique Identifiers for all study data. Master links to PHI will 
be maintained in a separate file maintained on a secure UNM computer and in Dr. 
Burge’s folder on the H drive.
16.7. If data will be coded, describe the nature of the code and mechanisms that will be 
used to protect the code (e.g., secure storage, limited access, separate location from 
research data).

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We will use the HRRC number plus a sequential number for all subjects who sign a 
consent form: 17-XXX-01, 17-XXX-02, etc.
16.8. Describe any procedures that will be used for quality control of collected data.
Data entered into spreadsheets or into REDCap will be randomly checked with source 
documents to assure accuracy. 
16.9. If data will be transferred or transmitted to outside locations or entities, describe:

What information will be included in that data or associated with the specimens?

Where and how data or specimens will be stored?

How long the data or specimens will be stored?

Who will have access to the data or specimens?

Who is responsible for receipt or transmission of the data or specimens?

How data and specimens will be transported?
Not applicable.
16.10.
Describe if data will be collected, transmitted, and/or stored via the internet, the 
identifiability of the data, and the security measures that will be employed to protect it.
Some data will be stored on the UNM HSC secure H drive, as is consistent with 
current guidelines.  Working data will be entered into REDCap through the UNM CTSC 
Biomedical Informatics Service.
16.11. Describe if data will be collected by audio or video recording, how the recordings will 
be secured, whether and when recordings will be transcribed, if the transcription will 
include identifiers, if, when, and how the recordings will be deleted.  Describe if the 
subjects will have the opportunity to review the recordings and request full or partial 
deletion. If the recordings may include persons other than the subjects, describe how 
this will be managed. 
Not applicable.
16.12. Describe if the data will include photographs, what will be included in the 
photographs, and how the photographs will be secured.  Describe if subjects will 
have the opportunity to review the photographs and request destruction.  If the 
photographs may include persons other than the subjects, describe how this will be 
managed. 
Not applicable.
17. Data and Specimen Banking
17.1. If data or specimens will be banked or archived locally for future use, provide the name 
and IRB number of the repository that they will be deposited into.  Describe exactly 
what data or specimens will be banked and for what purposes, and whether the data 
or specimens will include identifiers, be coded, or be fully stripped of all identifiers with 
no code or key that would allow relinking.  Be certain to describe the banking in the 
primary consent.  A separate consent and authorization, if applicable, will be 
necessary for the banking activity itself and is typically provided by the repository.  If 
you need to establish a repository for the purposes of banking or archiving data or 
specimens, a separate submission for the repository is needed as this is considered to 
be a distinct research activity under the regulations. 

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Not applicable.
17.2. If this is a multi-center study, and/or if data or specimens will be banked or archived 
elsewhere, identify who the holder of the data or specimens will be, exactly what data 
or specimens will be banked and for what purposes, and whether the data or 
specimens will include identifiers, be coded, or be fully stripped of identifiers with no 
code or key that would allow relinking.  A Materials Transfer or other agreement may 
be necessary, please consult with the HSC Sponsored Projects Office at 505-272-
6264 or by email at hsc-preaward@salud.unm.edu. Material Transfer Agreement 
procedures may be found at http://hsc.unm.edu/financialservices/preaward/ancillary-
agreements/material-transfer-agreements/procedures.html.   Be certain to describe the 
banking in the consent and authorization, using opt-in procedures, and the procedures 
for subjects to request withdrawal of their data or specimens and any limitations on 
their ability to do so. 
Not applicable.
18. Risks to Subjects
18.1. List the reasonably foreseeable risks, discomforts, hazards, or inconveniences to the 
subjects related the subjects’ participation in the research.  Describe the probability, 
magnitude, duration, and reversibility of the risks. Consider physical, psychological, 
social, legal, and economic risks.  Note that almost all research includes confidentiality 
risks.
Study medication risks: Participants may experience some side effects from the study 
medication.  Approximately 20% of patients experience gastrointestinal bloating with 
Metformin, but these symptoms tend to improve over time. Some of the more common side 
effects of metformin include abdominal or stomach discomfort, cough or hoarseness, 
decreased appetite, diarrhea, fast or shallow breathing, fevers or chills, a general feeling of 
discomfort, lower back or side pain, muscle pain or cramping, painful or difficult urination, 
and sleepiness.  Less common side effects of metformin include anxiety, blurred vision, 
chest discomfort, cold sweats, coma, confusion, cool or pale skin, depression, difficult or 
labored breathing, dizziness, fast or irregular or pounding or racing heartbeat, a feeling of 
warmth, headache, increased hunger, increased sweating, nausea, nervousness, redness 
of the face or neck or arms or upper chest, seizures, shortness of breath, slurred speech, 
tightness in the chest, unusual tiredness or weakness, or wheezing.  Rare side effects of 
metformin include a behavior change similar to being drunk, difficulty with concentration, 
drowsiness, lack or loss of strength, or restless sleep. 
There are no known serious side effects to the CaCO3 Placebo therapy.  There is a 
theoretical increased risk of kidney stones in a patient who is predisposed to them (< 1%).  
CaCO3 may also cause mild gas, bloating, or constipation in up to 30% of participants. 
CaCO3 may also interfere with the absorption of certain other drugs from your 
gastrointestinal 
tract. 
These 
medications 
include 
certain 
antibiotics 
(quinolones, 
tetracycline), certain osteoporosis medications (alendronate, residronate), heart and blood 
pressure medications (digoxin, diltiazem, verapamil, amlodipine), thyroid hormone 
(levothyroxine), and diuretics (hydrochlorothiazide).  Additionally, estrogen therapy might 
increase the absorption of CaCO3 from the gut.  For the most part, these effects can be 
avoided by taking the calcium at different times than the other medications. Subjects will be 

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instructed to report any side effects they experience while taking part in this study to their 
study doctor or study personnel.    
Blood drawing risks:  Drawing blood may cause temporary pain and discomfort from the 
needle stick.  Bruising at the site of the needle insertion, sweating, feeling faint or 
lightheaded and, in rare cases, infection may also occur.  There is also a < 1% chance of 
passing out briefly during blood draws. If this occurs, subjects will be asked to lie down and 
rest until they feel better.   All blood draws will occur in a clinical setting and will be 
performed by a phlebotomist who is trained in aseptic technique and in recognizing the 
signs of distress. After the blood draw, a bandage and care instructions will be provided.  In 
the event that the subject feels faint or shaky after the blood draw, they may be provided 
with a small snack.
According to common medical study guidelines, subjects should not donate too 
much blood at one time, and though the total amount of blood to be obtained during this 
12 week study is less than ½ of a typical blood donation, we will instruct the blood donor 
they should plan not to donate blood until after 8 weeks after the completion of the study.
Allergic reaction:  Although allergies to Metformin are rare, there is a risk of allergic 
reaction with any drug. Subjects will be advised of the symptoms of an allergic reaction that 
may include, but are not limited to, trouble breathing, fast heart rate, rash, dizziness, itching, 
and swelling. They will be instructed to contact the study team immediately, or present to the 
nearest emergency room if they experience any of these symptoms.
Bioelectrical Impedance Analysis:  This procedure has been shown to cause mild skin 
irritation from electrode adhesives, or temporary discomfort, although this is rare.   We will 
not perform this test in people with a lot of metal in their body (such as a metal hip or other 
joint replacement), those with amputations, those who have received radiographic contrast 
material within the last 72 hours, or people with coronary artery stents or metallic sutures, 
since these factors can interfere with the test results.
Reproductive Risks:  There are no known reproductive risks in this study, and Metformin has 
been used safely during pregnancy on many occasions.  Nevertheless, we will not recruit 
subjects in this study who are pregnant. Women of child-bearing age who are enrolled will be 
requested to employ an acceptable method of birth control (condoms or other barrier method, 
birth control pills, an IUD, or long-acting implantable contraception) for the duration of the study 
and to notify study personnel immediately if they become pregnant during the course of this 
study.  
General: There are risks of stress, emotional distress, inconvenience and possible loss of 
privacy and confidentiality associated with participating in any research study. Subjects will 
be informed that they can discuss these concerns and any others regarding the study by 
contacting the study doctor.
18.2. If applicable, indicate which procedures may have risks to the subjects that are 
currently unforeseeable.
Not applicable.

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18.3. If applicable, indicate which procedures may have risks to an embryo or fetus should 
the subject be or become pregnant.  If pregnancy testing or birth control provisions are 
required, describe these.
Metformin and CaCO3 have been used safely in many pregnancies, but pregnant 
women will not be allowed to participate in this study.
18.4. If applicable, describe risks to others who are not subjects.
Not applicable.
18.5. Describe the steps being taken to minimize the probability or magnitude of risks.
Metformin (1500 mg daily) and CaCO3 (1944 mg) are being titrated up to full dose 
slowly.
Note: All risks described here should also be described in the consent document.
19. Potential Benefits to Subjects
19.1. Describe the potential benefits that individual subjects may experience from taking part 
in the research. Include as may be useful for the IRB’s consideration, the probability, 
magnitude, and duration of the potential benefits.
19.2. Indicate if there is no direct benefit. Do not include benefits to society or others in this 
section.
Note: All potential benefits described here should also be described in the consent 
document.
Although some subjects may lose a small amount of weight with Metformin therapy, 
there may be no direct benefit to them from participating in this study.  However, it is 
hoped that information gained from this study will help in the future understanding and 
treatment of prediabetes and further, help us better understand whether or not 
Metformin might result in anti-aging effects on cells.
20. Recruitment Methods
20.1. Describe when, where, and how potential subjects will be recruited.
20.2. Describe the methods that will be used to identify potential subjects (e.g., chart review, 
referral, etc.). 
20.3. Describe materials that will be used to recruit subjects (e.g., emails, scripts, 
advertisements, brochures, flyers, etc.). Attach draft copies of the documents or audio 
or video recordings with the application. Once the draft has been approved, the final 
copy of the printed material, audio or video recording must be submitted for review and 
approval prior to implementation.  Please see Worksheet HRP-315 for information on 
advertisement standards.
We will recruit potential subjects with prediabetes from the Endocrinology Clinics, from 
the CTSC participant recruitment service, and from the UNM Prediabetes Cohort 
Registry. This latter registry is the result of a small CDC-sponsored study performed at 
UNM a few years ago that identified 104 subjects with prediabetes out of 218 at-risk 
subjects who were screened (HRRC # 11-422) [126]. These subjects agreed to be 
contacted in the event of future research involving prediabetes. We will also employ 

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CTSC-sponsored social media to recruit for this study, if necessary. We do not 
anticipate much difficulty identifying subjects who are interested in participating in this 
study. We estimate that 50 adults at risk for diabetes will need to be screened to find 
30 eligible subjects with prediabetes to enroll in this study.
21. Provisions to Protect the Privacy Interests of Subjects
21.1. Describe the steps that will be taken to protect subjects’ privacy interests. “Privacy” 
refers to persons and their interest in controlling the access that others have to 
themselves.  For example, based on their privacy interests, people may want to 
control:

The time and place/setting where they are examined or provide information

The nature of the information they provide

The nature of the experiences they are exposed to 

Who may observe or have access to information about them
For example, individuals may not want to be approached for participation, provide 
responses to a research interview, or undergo a research procedure in a location 
where they may be seen or overheard.
The CTSC Participant Recruitment Service maintains a “do not call” list, and we will 
abide by that request.  Calls to potential participants will be will be made during 
working hours.  If that proves unsuccessful in contacting patients, one or two calls 
might be made in the evening hours. Study personnel will describe the study and 
gauge the subject’s interest.  
21.2. Describe the steps that will be taken to protect subjects’ privacy including privacy 
protections during recruitment, consent, and data collection. Issues related to data are 
addressed in the Data Management/Confidentiality Section.
Contact information for subjects contacted through the Participant Recruitment Service 
who opt not to participate will be destroyed within three days, as per PRS policy. 
22. Economic Burden to Subjects
22.1. Describe any costs that subjects may be responsible for because of participation in the 
research.  Clearly stipulate what procedures are standard of care and what procedures 
are research-related in the table below. Please place an X in the box for the 
responsible party for each procedure involved.
List any costs to participants (or their 3rd party payer); include any charges for study 
procedures, visits, or drug/devices.
No costs will be incurred by study participants for this study.
Responsible Party
Research Procedures
Number of 
Samples & 
Procedures
Study
3rd Party 
Payer or 
Participant
     
     
     
     
     
     
     
     

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Responsible Party
Standard of Care Procedures
Number of 
Samples/Proced
ures
Study
3rd Party 
Payer or 
Participant
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
22.2. List any other costs to participants not already described above. 
Not applicable.
22.3. Indicate whether subjects will be charged for investigational drugs, devices, 
procedures.
Not applicable.
22.4. Explain who will be responsible for paying for treatment of adverse events.
Study subjects will assume responsibility for the costs related to adverse events, as 
per HRRC boilerplate.
22.5. Ensure that the cost section of the consent form reflects the cost that are covered by 
the sponsor and the costs for which the subjects (or 3rd party payers) are responsible.
Done.
23. Compensation
23.1. Describe any plans for compensation or reimbursement for subjects (amounts, 
methods (e.g., cash card), and payment schedule).  Describe why the proposed 
amount is reasonable and appropriate for the subjects’ time and inconvenience.  Credit 
for payment should be prorated and not be contingent upon the participant completing 
the entire study.  Any amount paid as bonus for completion of the entire study should 
not be so great that it could unduly induce subjects to remain in the study when they 
otherwise would have withdrawn.  Note: Consult with your department official for 
reporting requirements associated with cash or merchandise cards distributed to 
research subjects.
In return for time and effort participating in this study, subjects will be compensated up 
to $120 if they complete the study.  Specifically, a cash card worth $30 will be given for 
each of the four study visits. If they do not complete the study, they will be paid $30 for 
each visit completed. The method of payment will be via ClinCard administered by the 
CTSC.  We do not feel this is an amount that will unduly influence subjects to 

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participate or remain in the study when they otherwise would withdraw. If we are 
having difficulty enrolling patients because of the low rate of reimbursement, we may 
approach the HRRC to increase the amount being offered.
24. Compensation for Research-Related Injury
24.1. If the research involves more than Minimal Risk to subjects, describe the plan for 
compensation in the event of research related injury.
24.2. If subjects are responsible for seeking their own form of care for research-related 
injury, describe how this will be communicated and what options are available to 
participants.
“No commitment is made by the University of New Mexico Health Sciences Center 
(UNM HSC) to provide free medical care or money for injuries to participants in this 
study. If you are injured or become sick as a result of this study, UNM HSC will provide 
you with emergency treatment at your cost. It is important for you to tell your study 
doctor immediately if you have been injured or become sick because of taking part in 
this study. If you have any questions about these issues, or believe that you have been 
treated carelessly in the study, please contact the Human Research Review 
Committee (HRRC) at the University of New Mexico Health Sciences Center, 
Albuquerque, New Mexico 87131, (505) 272-1129 for more information.”  
25. Consent Process
25.1. Indicate whether you will you be obtaining consent, and if so describe:
25.1.1. Who will be responsible for obtaining consent and their qualifications/training to 
do so.  Be certain to identify which study team members will obtain consent in 
Click under Project Contacts.
Study personnel or CTSC personnel will obtain informed consent.
25.1.2. Where will the consent process take place and the provisions for privacy.
Informed consent will be obtained at the UNM CTSC Clinical Research Unit 
during the screening visit.  If participants desire more time to think about it, they 
will be granted that time. 
25.1.3. The steps that will be taken to minimize the possibility of coercion or undue 
influence.
We will make it clear that the study is entirely voluntary.
25.1.4. The waiting period available between reviewing the study and consent with the 
potential subject and obtaining the consent.
The study design is simple, so we feel that most potential participants will be 
ready to make a decision after having the study described and reviewing the 
consent form.  For those who require more time, they will be provided a copy of 
the consent form and allowed to return at their convenience, if desired. 
25.1.5. Processes to ensure ongoing consent throughout the study.
Any unhappy participants will be reminded that they have the right to withdraw 
from the study at any time.
25.1.6. Any steps that will be taken to enhance understanding.

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We will use the “teach-back” method to ensure that potential participants 
understand the study procedures.
25.1.7. Any procedure/testing for ensuring that the consent is understood by the 
potential subject (e.g., teach back).
We will use the “teach-back” method to ensure that potential participants 
understand the study procedures.
Subjects not fluent in English
25.1.8. Indicate what language(s) other than English are understood by prospective 
subjects or representatives.
We do not anticipate enrolling any “Spanish-language-only” patients in this study, 
but we may revisit this issue if we are having difficulty enrolling subjects.
25.1.9. If you anticipate enrolling subjects who do not understand or have limited fluency 
in English, describe the process to ensure that the oral and written information 
provided to those subjects initially and throughout their participation will be in the 
language they understand (e.g., use of translations and interpreters). Please note 
that translations of consent documents and subject materials will likely be 
required once the content of the English-language version is approved.
Not applicable.
25.1.10. Short-form consent documents are available for unanticipated enrollments of 
persons who don’t understand or have limited fluency in English.  However, 
based upon the nature of the research (e.g., clinical trials) subsequent translation 
of the consent document may be required so that the subject has access to 
written information about the research in a language they understand.
Not applicable.
Cognitively Impaired Adults/Adults Unable to Consent/Use of a Legally Authorized 
Representative
25.1.11. The IRB must specifically approve the enrollment of adults unable to consent 
and adults with cognitive impairment or limited decision-making capacity.  
Complete the applicable checklist in the Checklists Section of this Protocol 
Template.
We do not plan to enroll any cognitively disabled individuals into this study.
25.1.12. Describe whether the entire subject population or a portion of it is expected to 
have limited or no ability to provide legally effective consent.
No.
25.1.13. Describe the process to determine whether an individual is capable of consent. 
We will assess their ability to read the consent form and to describe study 
procedures to the study team.
25.1.14. Describe the process to determine whether a prospective subject is capable of 
providing consent.  Include who will be responsible for determining capacity and 
how it will be documented.

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All study team members who obtain informed consent will make the 
determination of fitness.  In the event of dispute, Dr. Burge will make the final 
decision. We will assess their ability to read the consent form and to describe 
study procedures to the study team. 
25.1.15. Describe how the participant’s decisional capacity will be assessed as the 
study proceeds in order to evaluate any fluctuation in the participant’s level of 
capacity to consent. 
We will assess their ability to read the consent form and to describe study 
procedures to the study team.
25.1.16. If it can be anticipated that some or all subjects will regain capacity to provide 
consent, describe the provisions to provide them with information about their 
participation in the research and to seek their consent for ongoing participation, if 
applicable.
Not applicable.
25.1.17. For research conducted in New Mexico, review “SOP: Legally Authorized 
Representatives, Children, and Guardians (HRP-013)” to be aware of which 
individuals in the state meet the definition of “legally authorized representative.”
Not applicable.
25.1.18. For research conducted outside of the New Mexico, provide information that 
describes which individuals are authorized under applicable law to consent on 
behalf of a prospective subject to their participation in the procedure(s) involved 
in this research. 
Not applicable.
25.1.19. Describe how the representative’s authority to provide consent will be 
confirmed. 
Not applicable.
25.1.20. Describe the process for assent of the subjects. Indicate whether:

Assent will be required of all, some, or none of the subjects. If some, indicated, which 
subjects will be required to assent and which will not.

If assent will not be obtained from some or all subjects, an explanation of why not.

Describe whether assent of the subjects will be documented and the process to 
document assent.
Not applicable.
Subjects who are not yet adults (infants, children, teenagers)
25.1.21. Provide the age range of the children anticipated to be enrolled in the research.
25.1.22. 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. 

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
For research conducted in New Mexico, review “SOP: Legally Authorized 
Representatives, Children, and Guardians (HRP-013)” to be aware of which 
individuals in the state meet the definition of “children.”

For research conducted outside of New Mexico, 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. 
25.1.23. Describe whether parental permission will be obtained from:

One parent (may be permissible, if the IRB approves, for (1) research not involving 
greater than minimal risk, or (2) research involving greater than minimal risk but 
presenting the prospect of direct benefit to individual subjects)

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. (Permissible for research involving greater than minimal risk 
and no prospect of direct benefit to individual subjects.)
25.1.24. Describe whether permission will be obtained from individuals other than 
parents, and if so, who will be allowed to provide permission. Describe the 
process used to determine these individuals’ authority to consent.
25.1.25. Indicate whether the children to be enrolled in the research should be capable 
of providing assent.
25.1.26. Indicate if assent will be obtained from all, some, or none of the children and 
provide justification.  If assent will be obtained from some children, indicate which 
children will be asked for assent.
25.1.27. When assent of children will be obtained describe the proposed assent process 
and whether and how assent will be documented.  The assent process and 
documentation of assent should be age-appropriate and may consist of different 
procedures for different age groups.
This section is not applicable to our study.
Waiver or Alteration of Consent Process (consent will not be obtained, required 
element of consent will not be included, or one or more required elements of 
consent will be altered) 

Complete the applicable checklists in the Checklists section of this Protocol 
Template if you are requesting a waiver or alteration of consent for this research

Consent can be waived for all of some subjects (e.g., the research includes a 
retrospective cohort)

Consent can be waived in full or in part (e.g., partial waiver for recruitment purposes)
Not applicable.
26. Documentation of Consent

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26.1. Describe if you plan to use a consent form to document consent.  Use the UNM HSC 
consent generator or one of the consent templates available on the HRPO website.  
Attach consent documents as fully editable Word documents (i.e., please don’t submit 
protected documents or pdfs).  Please include page numbers in the footer (e.g., Page 
1 of XX).
Consent form attached.
26.2. If the study is collecting and/or storing tissue samples, include a Tissue Banking 
Consent Form (and Authorization if the specimens will be accompanied by PHI).
Not applicable.
26.3. Describe if you plan to obtain consent but will be using a script, information sheet, or 
other mechanism.  If you will obtain consent verbally, attach a consent script and 
information sheet, if you will be providing one.  If you will be obtaining consent via an 
on-line survey, please use the survey cover letter consent template on the HRPO 
website and include your email script with your submission. 
Complete the checklist for “Waiver of Documentation of Consent” in the Checklists 
section of this Protocol Template.  If you will be excluding or modifying one or more of 
the required elements of consent you will also need to request an Alteration of 
Consent.
We will not use a script.  We will describe the study and then let subjects review the 
consent form.  We will then offer to answer any questions the participant has, and we 
will quiz the subject about a few aspects of the study.
27. Study Test Results/Incidental Findings
27.1. Individual Results: Indicate whether you intend to share study test or procedure 
results with study participants.  If so, describe which results will be shared, whom the 
results will be shared with (e.g., subjects, parents, primary care physicians), and how 
the findings will be communicated (e.g., in person consultation, posting in medical 
record, etc.).  If the findings are the results of laboratory tests, indicate whether the 
tests will be processed in a CLIA-certified lab.  
We will use CLIA and/or CAP-certified laboratories.  Participant A1c lab results upon 
request.  
27.2. Incidental Findings: Based upon the nature of the research, and the tests that will be 
performed, indicate if you anticipate that the research may result in incidental findings 
(traditionally defined as results that arise that are outside the original purpose for which 
the test or procedure was conducted (for example, a potential tumor is identified but 
this is not the reason imaging was obtained).  If so, please describe your plans for 
communication of such results to subjects and their health care providers, if 
appropriate.  If there are limitations on the accepted validity of the results (e.g., test 
performed in non-CLIA lab, test available in the context of research only), please 
describe and provide a plan for confirmatory testing or justification for why it is not 
recommended, not necessary, or not possible.  If you do not plan to provide results, 
provide justification.  

Be certain to describe your plans for provision of study results and incidental findings 
in your consent documents.

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
For more information on incidental findings, please consult the President’s Bioethics 
Commission Report “Anticipate and Communicate: Ethical Management of Incidental 
and Secondary Findings in the Clinical, Research, and Direct-to-Consumer 
Contexts”: 
http://bioethics.gov/sites/default/files/FINALAnticipateCommunicate_PCSBI_0.pdf 

For information specific to Whole Genome Sequencing, please consult the 
President’s Bioethics Commission Report “Privacy and Progress in Whole Genome 
Sequencing”: http://bioethics.gov/sites/default/files/PrivacyProgress508_1.pdf 
If any information becomes available that alters the risk/benefit ratio of this short 
study, we will inform the HRRC and participants by phone, personal interaction in the 
CTSC, or via telephone, personal interaction, or letter. 
28. Sharing Study Progress or Results with Subjects
28.1. Describe whether you intend to provide subjects with a summary of the trial progress 
while the study remains underway.  If so, describe your plans and the mechanisms 
that you will use (e.g., newsletter, handouts, mailings, etc.).  Please note that all 
written materials that will be provided to subjects need to be reviewed and approved 
by the IRB prior to use.
28.2. Describe whether you intend to provide subjects with a summary of the study results 
after the study is complete.  If so, indicate if the information will include study arm 
assignment if the study involved blinding.  Please describe your plans for 
dissemination of results and the mechanisms that you will use.  Please note that IRB 
review of materials may be required, consult with the HRPO prior to distribution.
We do not plan to provide subjects with a summary of the study progress or findings.  
A copy of publications resulting from this study will be provided to participants who 
request it.
29. Inclusion of Vulnerable Populations
29.1. If the research involves individuals who are vulnerable to coercion or undue influence, 
describe who will be included, why their participation is necessary or warranted, and 
any additional safeguards included to protect their rights and welfare. The following is 
not intended to serve as a comprehensive list, rather to provide some examples for 
your consideration.
29.1.1. If the research includes students or employees, describe protections to 
promote the voluntary nature of participation and minimize the risks 
associated with access to or use of data by persons in a position of actual or 
perceived authority. 
29.1.2. If the research includes economically disadvantaged persons, describe the 
mechanisms to promote the voluntary nature of participation and to minimize 
economic risks associated with participation.
29.1.3. If the research includes educationally disadvantaged persons, describe the 
mechanisms to ensure that they are provided information and materials that 
enhance their ability to understand the research initially and throughout their 
participation in the research.

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29.1.4. If the research includes seriously or terminally ill patients, describe the 
mechanisms to ensure that they understand the true purposes of the 
research, the risk it entails, and what is known or not understood about the 
likelihood of individual benefit
29.1.5. If the research involves pregnant women, note this here and complete the 
Pregnant Women Checklist in the Checklist Section of this Protocol 
Template.  
29.1.6. If the research involves neonates of uncertain viability or non-viable 
neonates, note this here and complete the applicable checklist in the 
Checklist Section of this Protocol Template.  
Note: For the purposes of the federal research regulations, viability is 
established shortly after delivery. “Viable, as it pertains to the neonate, 
means being able, after delivery, to survive (given the benefit of available 
medical therapy) to the point of independently maintaining heartbeat and 
respiration.” Once a neonate has been determined viable, they are 
considered a child under the regulations.
29.1.7. If the research involves prisoners, note this here and complete the Prisoners 
Checklist in the Checklist Section of this Protocol Template.  
29.1.8. If the research involves persons who have not attained the legal age for 
consent to treatments or procedures involved in the research (“children”), 
note this here and complete the Children Checklist in the Checklist Section of 
this Protocol Template.  
29.1.9. If the research involves cognitively impaired adults, note this here and 
complete the Cognitively Impaired Adults Checklist in the Checklist Section of 
this Protocol Template.
We do not plan to recruit or enroll members of vulnerable populations in this study.
30. Community-Based Participatory Research
30.1. Describe involvement of the community in the design and conduct of the research.  If 
members of the community will fulfill key research responsibilities such as recruitment 
and consent, describe what research activities community members will be 
responsible for, how they will be trained, and the plan for quality oversight.  When 
relevant, please include information regarding the approval of the research at 
collaborating sites (e.g., Albuquerque Public Schools).
Note: “Community-based Participatory Research” is a collaborative approach to 
research that equitably involves all partners in the research process and recognizes 
the unique strengths that each brings. Community-based Participatory Research 
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.
Not applicable.
31. Research Involving American Indian/Native Populations
31.1. Please provide detailed information of the local research context including how the 
research questions are sensitive to community attitudes and how the PI has 

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ascertained that the proposed research is acceptable to the local population in terms 
of tribal regulations, applicable law and standards of professional conduct and 
practice.  Attach any supporting documents from tribal officials or entities addressing 
the status or requirements for review of the research activity from tribal officials or 
tribal entities (for example, Indian Health Services, the Navajo Nation IRB).  
This research proposal is not specifically geared toward members of any one 
community, nor will we exclude members of any community. As American 
Indian/Native populations do experience significant levels of prediabetes, however, 
and as our local population includes a significant number of Native American persons, 
we expect that our research recruitment will include subjects from this population and 
that our findings would be applicable and of interest to them.
32. Transnational Research
32.1. When conducting transnational research, you must ensure that subjects are provided 
equivalent and appropriate protections for human subjects located outside of the 
United States.  Please refer to the following website for current OHRP interpretations 
of research standards, equivalent protections, and for a current compilation of 
international research standards and regulatory agencies. 
http://www.hhs.gov/ohrp/international/index.html 
32.2. Location: Describe the research locale and how and why the setting was chosen.  
Describe significant cultural norms, local laws, and differences with U.S. culture with 
respect to autonomy, perception of research, recruitment, consent, age of majority, 
parental permission, etc.  
32.3. Study Personnel: Describe the qualifications of the researcher and research team to 
perform research in the community/culture where it will occur.  Indicate the research 
team’s ability to speak, read, and write the language of the subjects.  Describe the 
researcher’s knowledge of or expertise in local or state laws, culture, and community 
norms. Indicate if the researcher was invited into the community (provide 
documentation, if available).  If not invited, then describe how the researcher will have 
culturally appropriate access to the community.
32.4. Consent: Describe the consenting procedure that you intend to use for the research 
and why it is appropriate for the community where the research will occur.  Describe 
how you will ensure that potential subjects understand the research, and the 
voluntariness of their participation.
32.5. Community Consultation: Describe any plans for community consultation to assess 
receptiveness to the proposed research and to obtain feedback on how it should be 
conducted and any limitations or boundaries that should be respected.  Describe plans 
for dissemination of results to subjects and to the community. 
Not applicable.
33. Drugs or Devices
33.1. If the research involves drugs or devices, 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.
We will use the UNM Investigational Pharmacy to package, label and deliver study 
drug.  Study drug may be stored in the CTSC pharmacy for 1 or 2 days prior to 

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participant appointments. After randomization, all subjects will receive study 
medication in the form of either Metformin or Placebo (i.e.- nearly identical CaCO3) as 
prepared and labelled by the UNM Hospital research pharmacist, Susan Kunkel, 
PharmD.  Subjects who choose to withdraw from the study will be required to return 
unused study medications provided to them.  Metformin has an excellent long-term 
safety record and is already FDA approved for utilization in the setting of prediabetes.  
As such, attainment of an FDA IND is not necessary for this study.
33.2. If the drug is investigational (has an IND), identify the holder of the 
IND/IDE/Abbreviated IDE.
No IND is necessary. Meformin is currently approved for use in prediabetes.  CaCO3 
Placebo has no known anti-diabetes activity.
33.3. For research involving drugs, complete and attach a signed “Drug Attachment”, 
available in Click or the HRPO website.
A signed “Drug Attachment” form is attached.
33.4. For research involving devices, complete the “Device Checklist” in the Checklist 
Section of this template.
Not applicable.
Checklist Section
This section contains checklists to provide information on a variety of topics that require special 
determinations by the IRB.  Please complete all checklists relevant to your research.
I.
Waivers or Alterations of Consent, Assent, and HIPAA Authorization
A. Partial Waiver of Consent for Screening/Recruitment
Complete this checklist if you are requesting a partial waiver of consent so that you 
can review private information to identify potential subjects and/or determine 
eligibility prior to approaching potential subjects for consent or parental permission.
Not applicable.
1.
Describe the data source that you need to review (e.g., medical records):
     
2.
Describe the purpose for the review (e.g., screening):
     
3.
Describe who will conducting the reviews (e.g., investigators, research staff):
     
4.
Do all persons who will be conducting the reviews already have permitted 
access to the data source?

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 Yes
 No. Explain:      
5.
Verify that each of the following are true or provide an alternate justification 
for the underlined regulatory criteria:
a) The activity involves no more than minimal risk to the subjects 
because the records review itself is non-invasive and the results of the 
records review will not be used for any purposes other than those 
described above.
 True
 Other justification:      
b) The waiver or alteration will not adversely affect the rights and welfare 
of the subjects because eligible subjects will be approached for 
consent to participate in the research and are free to decline.  Further, 
the information accessed during the records review will not be 
disclosed to anyone without a legitimate purpose (e.g., verification of 
eligibility).
 True
 Other justification:      
c)
The research could not practicably be carried out without the waiver 
or alteration because there is no other reasonably efficient and 
effective way to identify who to approach for possible participation in 
the research.  
 True
 Other justification:      
d) Whenever appropriate, potentially eligible subjects will be presented 
with information about the research and asked to consider 
participation.  (Regulatory criteria: Whenever appropriate, the subjects 
will be provided with additional pertinent information after 
participation.)
 True
 Other justification:      
Partial Waiver of HIPAA Authorization for Screening/Recruitment
Complete the following additional questions/attestations if the records you will review 
to identify potential subjects and/or determine eligibility include Protected Health 
Information (PHI).
6.
Will you be recording any PHI when conducting the records review to identify 
potential subjects and/or determine eligibility?
 Yes. Describe: Name, contact information, Medical Record Number. 

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 No
7.
If you answered “Yes” to question 6 above, please describe when you will 
destroy identifiers (must be the earliest opportunity consistent with the 
conduct of the research) or provide justification for why they must be 
retained:
Identifiers will be destroyed upon closure of the study.
8.
The PHI accessed or recorded for identification/screening purposes will not 
be reused or disclosed to (shared with) any other person or entity, except as 
required by law, for authorized oversight of the research study, or for other 
research for which the use or disclosure of the PHI would be permitted under 
the Privacy Rule.
 True
 False
B. Waiver of Documentation of Consent
Complete this checklist if you intend to obtain consent verbally but will not be 
obtaining signatures from subjects on a consent form to document consent.  Waivers 
of documentation of consent are commonly requested when using scripts, 
information sheets, or email or survey introductions to present the elements of 
consent instead of using a traditional consent form.
Not applicable.
1.
Are you requesting a waiver of documentation of consent for some or all 
subjects?
 All
 Some. Explain:      
2.
Provide justification for one of the following:
a) That the only record linking the subject and the research would be the 
consent document and the principal risk would be potential harm 
resulting from a breach of confidentiality. Each subject will be asked 
whether the subject wants documentation linking the subject with the 
research, and the subject's wishes will govern.
     
b) That the research presents no more than minimal risk of harm to 
subjects and involves no procedures for which written consent is 
normally required outside of the research context.
     

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3.
Do you intend to provide subjects with a written statement regarding the 
research in lieu of a traditional consent form?
 Yes. Please attach a copy to your submission in Click.
 No
C. Alteration of Consent
Complete this checklist if you intend to obtain consent but will be eliminating or 
altering one or more of the required elements of consent. Alterations of consent are 
commonly requested for research involving deception or for minimal risk research 
when an abbreviated consent is desired and one or more of the required element are 
not relevant to the research.
Not applicable.
Note: FDA-regulated research is not eligible for an alteration of consent.
1.
Which element(s) of consent do you wish to eliminate and why?
     
2.
Which element(s) of consent do you wish to alter and why?
     
3.
Provide justification for each of the following regulatory criteria:
a) The research involves no more than minimal risk to the subjects:
     
b) The waiver or alteration will not adversely affect the rights and welfare 
of the subjects:
     
c)
The research could not practicably be carried out without the waiver 
or alteration:
     
d) Whenever appropriate, the subjects will be provided with additional 
pertinent information after participation:
     
D. Full Waiver of Consent/Parental Permission
Complete this checklist if you are requesting a full waiver of consent for all subjects 
or certain subject groups (e.g., retrospective cohort).  Full waivers of consent are 
commonly requested when the research does not include any opportunity for 
interaction with subjects (e.g., chart review).

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Note: FDA-regulated research is not eligible for a full waiver of consent using these 
criteria.  If you believe that your FDA-regulated research may be eligible for a waiver 
under another mechanism, such as planned emergency research, contact the HRPO 
for assistance in determining what information to provide to the HRRC.
Not applicable.
1.
Are you requesting a waiver for some or all subjects?
 All
 Some. Explain:      
2.
Provide justification for each of the following regulatory criteria:
a) The research involves no more than minimal risk to the subjects:
     
b) The waiver or alteration will not adversely affect the rights and welfare 
of the subjects:
     
c)
The research could not practicably be carried out without the waiver 
or alteration:
     
d) Whenever appropriate, the subjects will be provided with additional 
pertinent information after participation:
     
E. Full Waiver of Consent/Parental Permission (Public Benefit or Service 
Programs)
Complete this checklist if you are requesting a full waiver of consent for all subjects 
or certain subject groups (e.g., retrospective cohort) and the research involves the 
evaluation of a public benefit or service program.  
1.
Are you requesting a waiver for some or all subjects?
 All
 Some. Explain:      
2.
Provide justification for each of the following regulatory criteria:
a) The research or demonstration project is to be conducted by or 
subject to the approval of state or local government officials and is 
designed to study, evaluate, or otherwise examine: (i) public benefit or 
service programs; (ii) procedures for obtaining benefits or services 
under those programs; (iii) possible changes in or alternatives to 
those programs or procedures; or (iv) possible changes in methods or 
levels of payment for benefits or services under those programs:

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b) The research could not practicably be carried out without the waiver 
or alteration.
     
F. Full Waiver of HIPAA Authorization
Complete this checklist if you are requesting a full waiver of the requirement to obtain 
HIPAA authorization for all subjects or certain subject groups (e.g., retrospective 
cohort).  Full waivers of HIPAA authorization are commonly requested when the 
research does not include any opportunity for interaction with subjects (e.g., chart 
review).
1.
Are you requesting a waiver of authorization for some or all subjects?
 All
 Some. Explain: Medical records at UNM.
2.
Describe your plan to protect health information identifiers from improper use 
and disclosure:
A master key to link unique identifiers will be maintained in a separate file on 
a secure UNM computer and the H drive in Dr. Burge’s folder.
3.
Describe your plan to destroy identifiers at the earliest opportunity consistent 
with conduct of the research (absent a health or research justification for 
retaining them or a legal requirement to do so):
Identifiers will be destroyed when the study is closed.
4.
Describe why the research could not practicably be conducted without the 
waiver or alteration:
Retention of identifiers helps make sure participants qualify for the study, 
allows the study team to make certain of drugs and doses that the patient is 
receiving, facilitates communication with the participant, and enhances 
participant safety.
5.
The PHI accessed or recorded for identification/screening purposes will not 
be reused or disclosed to (shared with) any other person or entity, except as 
required by law, for authorized oversight of the research study, or for other 
research for which the use or disclosure of the PHI would be permitted under 
the Privacy Rule.
 True
 False
G. Other Waiver Types
If you are seeking another waiver type (e.g., Planned Emergency Research, Waiver 
of Parental Permission to Protect Child Participants, Enforcement Discretion for In 

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Vitro Diagnostics, etc. contact the HRPO office for assistance in determining what 
information to submit for the HRRC’s consideration.
Not applicable.
II.
Vulnerable Populations
A. Adults with Cognitive Impairments
Complete this checklist if the subject population will include adults with cognitive 
impairments.  
This checklist does not need to be completed if the research doesn’t involve 
interactions or interventions with subjects and will be conducted under a waiver of 
consent.
1.
Describe why the objectives of the study cannot be met without inclusion of 
adults with cognitive impairments.
     
2.
Describe how capacity to consent will be evaluated.
     
3.
If subjects may regain capacity to consent, or if subjects may have fluctuating 
capacity to consent, describe your plans to evaluate capacity to consent 
throughout the research and to obtain consent to continue participation if 
capacity is regained.
     
4.
Describe your plans, if any, to provide information about the research to 
subjects and the steps you will take to assess understanding.
     
5.
Describe your plans to obtain assent, including whether assent will be 
obtained from none, some, or all subjects.
     
6.
Describe why risks to subjects are reasonable in relation to anticipated 
benefits to the subjects.
     
7.
If this study involves a health or behavioral intervention, describe why the 
relation of the anticipated benefit to the risk of the research is at least as 
favorable to the subjects as that presented by alternative procedures.
     

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8.
Describe your plans for monitoring the well-being of subjects including any 
plans to withdraw subjects from the research if they appear to be unduly 
distressed.
     
B. Children
Complete this checklist if the subject population will include children.
1.
Select the category of research that you believe this research falls within and 
provide justification for any associated criteria.  If there are different 
assessments for different groups of children or arms (e.g., placebo vs. drug), 
include a memo to provide an assessment for each group.  
 Research not involving greater than minimal risk. (Minimal risk means 
that the probability and magnitude of harm or discomfort anticipated in 
the research are not greater in and of themselves than those 
ordinarily encountered in daily life or during the performance of routine 
physical or psychological examinations or tests.)
 Research involving greater than minimal risk but presenting the 
prospect of direct benefit to the individual subjects.
Provide justification for each of the following criteria:
(1) The risk is justified by the anticipated benefit to the subjects:
     
(2) The relation of the anticipated benefit to the risk is at least as 
favorable to the subjects as that presented by available 
alternative approaches:
     
 Research involving greater than minimal risk and no prospect of direct 
benefit to individual subjects, but likely to yield generalizable 
knowledge about the subject's disorder or condition.
Provide justification for each of the following criteria:
(1) The risk represents a minor increase over minimal risk:
     
(2) The intervention or procedure presents experiences to 
subjects that are reasonably commensurate with those 
inherent in their actual or expected medical, dental, 
psychological, social, or educational situations:
     
(3) The intervention or procedure is likely to yield generalizable 
knowledge about the subjects' disorder or condition which is of 

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vital importance for the understanding or amelioration of the 
subjects' disorder or condition
     
C. Pregnant Women and Fetuses
Complete this checklist if the subject population will include pregnant women and 
fetuses.
This checklist does not need to be completed if the research is both minimal risk and 
is not conducted, funded, or otherwise subject to regulation by DHHS, DOD, EPA, or 
VA.
Provide justification for each of the following:
1.
Where scientifically appropriate, preclinical studies, including studies on 
pregnant animals, and clinical studies, including studies on non-pregnant 
women, have been conducted and provide data for assessing potential risks to 
pregnant women and fetuses.
Our numbers are too small to provide meaningful data on use of Metformin or 
CaCO3 in pregnancy.
2.
The risk to the fetus is caused solely by interventions or procedures that hold 
out the prospect of direct benefit for the woman or the fetus; or, if there is no 
such prospect of benefit, the risk to the fetus is not greater than minimal and 
the purpose of the research is the development of important biomedical 
knowledge which cannot be obtained by any other means.
No pregnant women will be enrolled.
3.
Any risk is the least possible for achieving the objectives of the research.
No pregnant women will be enrolled.
D. Neonates of Uncertain Viability or Nonviable Neonates
Complete this checklist if the subject population will include neonates of uncertain 
viability.
Provide justification for each of the following:
1.
Where scientifically appropriate, preclinical and clinical studies have been 
conducted and provide data for assessing potential risks to neonates.
     
2.
Each individual providing consent is fully informed regarding the reasonably 
foreseeable impact of the research on the neonate.
     
3.
Individuals engaged in the research will have no part in determining the 
viability of a neonate.

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4.
The research holds out the prospect of enhancing the probability of survival 
of the neonate to the point of viability, and any risk is the least possible for 
achieving that objective, or, the purpose of the research is the development 
of important biomedical knowledge which cannot be obtained by other means 
and there will be no added risk to the neonate resulting from the research
     
E. Nonviable Neonates
Complete this checklist if the subject population will include nonviable neonates.
Provide justification for each of the following:
1.
Where scientifically appropriate, preclinical and clinical studies have been 
conducted and provide data for assessing potential risks to neonates.
     
2.
Each individual providing consent is fully informed regarding the reasonably 
foreseeable impact of the research on the neonate.
     
3.
Individuals engaged in the research will have no part in determining the 
viability of a neonate.
     
4.
The purpose of the research is the development of important biomedical 
knowledge that cannot be obtained by other means.
     
Verify each of the following:
5.
Vital functions of the neonate will not be artificially maintained
 True
 False
6.
The research will not terminate the heartbeat or respiration of the neonate
 True
 False
7.
There will be no added risk to the neonate resulting from the research
 True
 False

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F. Biomedical and Behavioral Research Involving Prisoners
Complete this checklist if the subject population will include prisoners.
Note: Minimal risk for research involving prisoners is the probability and magnitude of 
physical or psychological harm that is normally encountered in the daily lives, or in 
the routine medical, dental, or psychological examination of healthy persons.
1.
Select and justify which allowable category of research involving prisoners 
this research falls within:
 Study of the possible causes, effects, and processes of incarceration, and 
of criminal behavior, provided that the study presents no more than 
minimal risk and no more than inconvenience to the subjects
     
 Study of prisons as institutional structures or of prisoners as incarcerated 
persons, provided that the study presents no more than minimal risk and 
no more than inconvenience to the subjects
     
 Research on conditions particularly affecting prisoners as a class (for 
example, vaccine trials and other research on hepatitis which is much 
more prevalent in prisons than elsewhere; and research on social and 
psychological problems such as alcoholism, drug addiction, and sexual 
assaults)
     
 Research on practices, both innovative and accepted, which have the 
intent and reasonable probability of improving the health or well-being of 
the subject
     
 Epidemiologic studies in which the sole purpose is to describe the 
prevalence or incidence of a disease by identifying all cases or to study 
potential risk factor associations for a disease, the research presents no 
more than Minimal Risk and no more than inconvenience to the subjects, 
and Prisoners are not a particular focus of the research.
     
2.
Provide justification for each of the following regulatory criteria:
a) Any possible advantages accruing to the prisoner through his or her 
participation in the research, when compared to the general living 
conditions, medical care, quality of food, amenities and opportunity for 
earnings in the prison, are not of such a magnitude that his or her 
ability to weigh the risks of the research against the value of such 
advantages in the limited choice environment of the prison is impaired

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b) The risks involved in the research are commensurate with risks that 
would be accepted by nonprisoner volunteers
     
c)
Procedures for the selection of subjects within the prison are fair to all 
prisoners and immune from arbitrary intervention by prison authorities 
or prisoners. Unless justification is provided, control subjects must be 
selected randomly from the group of available prisoners who meet the 
characteristics needed for that particular research project
     
d) The information is presented in language which is understandable to 
the subject population
     
e) Adequate assurance exists that parole boards will not take into 
account a prisoner's participation in the research in making decisions 
regarding parole, and each prisoner is clearly informed in advance 
that participation in the research will have no effect on his or her 
parole
     
f)
When appropriate, adequate provision has been made for follow up 
examination or care after research participation, taking into account 
the varying lengths of individual prisoners' sentences, and for 
informing participants of this fact
     
III. Medical Devices
Complete this checklist if the research evaluates the safety or effectiveness of a medical device.  
If more than one medical device is being evaluated, provide the requested information for each.
A. Device Name:       
B. Manufacturer:       
C. Does the research involve a Significant Risk Device under an IDE?
 Yes. Include documentation of the FDA approval of the IDE with your submission.  
Acceptable methods of documentation include: (1) FDA letter noting IDE number and 
approval status; (2) Industry sponsor letter noting IDE number and FDA approval 
status; or (3) FDA-approved industry sponsor protocol with IDE number noted 
 No

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D. Is the research IDE-exempt?
 Yes. Include a FDA letter with your submission noting the determination that the 
research is IDE-exempt or a letter from the sponsor (or sponsor-investigator) 
justifying why they believe the research is IDE-exempt*.  
 No
E. Does the research involve a Non-Significant Risk (NSR) Device?
 Yes. Include a FDA letter with your submission noting the determination that the 
research is NSR or a letter from the sponsor (or sponsor-investigator) justifying why 
they believe the research is NSR**.  
 No
* This FDA guidance includes a description for when a device study is exempt from the 
IDE requirements: 
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM127067.pdf 
**This FDA guidance includes information on how to differentiate between Significant 
Risk and Non-Significant Risk device studies: 
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126418.pdf