Clinical trial NCT02986659
Conditions: Coronary Artery Disease Mild Cognitive Impairment Obesity, Abdominal Hypertension
Sponsor: Wake Forest University Health Sciences
Start date: 2016-08-03; Completion date: 2018-11-15
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Medical scientists have found that people with diabetes who take the drug Metformin have less age-related disease than those taking other treatments and researchers believe it may prevent numerous diseases and conditions that effect older people. In addition, metformin extends lifespan in some animal models of human disease. The purpose of this study is to see if taking Metformin causes changes in blood cells consistent with improved health and longevity in people who do not have diabetes. In this study Metformin will be compared to placebo. A placebo is a substance, like a sugar pill, that is not thought to have any effect on a participants disease or condition. In this study participants will either receive the active study medication, Metformin or placebo which is not active. Placebos are used in research studies to see if the drug being studied really does have an effect.

Detailed description:
The number of older adults is projected to increase dramatically by 2050. Aging-related diseases and conditions still seriously compromise the quality of life among most older adults. Several pharmaceutical agents, such as metformin, have been tested to extend lifespan and delay aging-related diseases and dysfunctions in mice. Metformin, a biguanide antidiabetic drug, reduces the risk for developing type-2 diabetes in persons at risk by over one-third with few adverse effects (e.g., gastrointestinal irritation). Metformin prevents type-2 diabetes primarily through decreasing hepatic glucose synthesis, as well as enhancing insulin sensitivity and increasing peripheral glucose uptake. The molecular mechanisms remain unclear, although a number of potential mechanism such as activation of AMP-activated protein kinase (AMPK) and inhibition of mitochondrial glycerophosphate dehydrogenase have been proposed. The fact that metformin treatment in persons with type-2 diabetes has been associated with reduced risk of other aging-related diseases and conditions, including cardiovascular disease, cancer and cognitive decline supports the possibility of the beneficial effects of metformin on healthy aging. It is imperative to capitalize on these leads to extend health span among older adults.

To translate animal findings to human intervention trials, appropriate aging biomarkers are needed. Methylomic and transcriptomic profiles in relevant cells may reflect molecular features that mediate effects of both genetic and environmental factors on aging-related functional decline and disease. The roles of monocytes have been implicated in development of many aging-related diseases such as cardiovascular disease, cancer and neurodegenerative disease. In a cross-sectional association study of 1,200 monocyte samples, we identified 1,794 age-associated methylation sites and 2,704 age-associated transcripts, which were over-represented in two networks (autophagy and oxidative phosphorylation) and suggestive of decline in those functions with age. Both autophagy and oxidative phosphorylation are considered as key contributors to the aging process, and their dysfunctions have been linked to aging-related diseases. Changes in these aging-related omic biomarkers may be early indicators of cellular damage or disruption that eventually leads to age-related dysfunctions. Assessment of these aging biomarkers in response to therapeutic intervention may also provide molecular insight for personalizing treatment. The investigators propose a pilot study to examine changes in aging-related omic profiles after 3 months of metformin treatment in 35 monocyte samples from older adults using a randomized, double-blind, placebo-controlled crossover study design.

Our overarching goal of the pilot study is to evaluate the utility of using the aging-related omic biomarkers as an indicator of pharmacologic responses in the anti-aging therapeutic intervention trials through the following specific aims. Although this pilot study does not have sufficient power to definitively test all the aims, it will provide essential preliminary data for developing a full scale research program.

* Aim 1A: To test the effects of the metformin treatment on transcriptomic profiles and related functional changes in human monocytes,
* Aim 1B: To explore the effects of the metformin treatment on methylomic profiles in human monocytes,
* Aim 2: To investigate the longitudinal relationship between transcriptional and functional changes in human monocytes during the metformin treatment and
* Aim 3: To test the effects of the metformin treatment on frailty and other aging-related physical and cognitive measures and investigate the longitudinal relationship between these changes and transcriptional changes.

A randomized, double-blind, placebo-controlled crossover trial in 30 participants using metformin and matching placebo will be used. In the absence of a treatment by sequence interaction effect, this design can increase study power for evaluating treatment effects by allowing each participant to be his/her own control. The period effect may be minimum because the primary outcomes, methylation and transcriptional measures, are relatively stable overtime.

Arms: arm 1: Metformin dosing at 425, 850 and 1700 mg with GLUCOPHAGE® (metformin hydrochloride) Tablets. Treatment with metformin will be initiated at a dose of 425 mg (half pill) taken orally once a day at night for 7 days. After the week, the participant will be called to assess tolerance and will be asked to increase dose to one pill at night at a dose of 850 mg for one week. At the end of the second week, participants will be called again and if they tolerated the second dose, they will be asked to take two 850 mg pills, one in the morning and one at night, for a total dose of 1700 mg which is within the range of the usual effective dose of 1500 to 2000 mg/day for the remainder of the 3 months. Will then cross over to 3 months on placebo. arm 2: Dietary Supplement: Placebo with Methylcellulose capsules. Treatment with placebo will be initiated at a dose of a half pill taken orally once a day at night for 7 days. After the week, the participant will be called to assess tolerance and will be asked to increase dose to one pill at night for one week. At the end of the second week, participants will be called again and if they tolerated the second dose, they will be asked to take two pills, one in the morning and one at night for the remainder of the 3 months. After 3 months on placebo, participants will then cross over to 3 months of metformin as described in the other arm.
Interventions: intervention 1: Metformin intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
NCT02986659 
Date: 9/4/2018 
 
Study Title: Genomic Outcomes of Metformin (GO MET) 
 
Principal Investigator, Co-investigator(s): Jingzhong Ding, Yongmei Liu, Barbara Nicklas, Stephen 
Kritchevsky, William Applegate, Mike Miller, Jamie Justice, Anthony Molina, and Don McClain 
 
Sponsor or funding source: Wake Forest Claude D Pepper Center 
 
Background, Rationale and Context 
The number of older adults is projected to increase dramatically by 2050.  Aging-related diseases and 
conditions still seriously compromise the quality of life among most older adults.  Several pharmaceutical 
agents (1-4), such as metformin, have been tested to extend lifespan and delay aging-related diseases and 
dysfunctions in mice. Metformin, a biguanide antidiabetic drug, reduces the risk for developing type-2 
diabetes in persons at risk by over one-third with few adverse effects (e.g., gastrointestinal irritation) (5).  
Metformin prevents type-2 diabetes primarily through decreasing hepatic glucose synthesis (6), as well as 
enhancing insulin sensitivity and increasing peripheral glucose uptake (7-9).  The molecular mechanisms 
remain unclear, although a number of potential mechanism such as activation of AMP-activated protein 
kinase (AMPK) and inhibition of mitochondrial glycerophosphate dehydrogenase have been proposed, 
see figure 1 (10;11).  The fact that metformin treatment in persons with type-2 diabetes has been 
associated with reduced risk of other aging-related diseases and conditions, including cardiovascular 
disease (12), cancer (13) and 
cognitive decline (14) supports 
the possibility of the beneficial 
effects of metformin on healthy 
aging.  It is imperative to 
capitalize on these leads to extend 
health span among older adults.    
 
 
To translate animal findings to 
human intervention trials, 
appropriate aging biomarkers are 
needed. Methylomic and 
transcriptomic profiles in relevant 
cells may reflect molecular 
features that mediate effects of 
both genetic and environmental 
factors on aging-related 
functional decline and disease. 
The roles of monocytes have 
been implicated in development 
of many aging-related diseases 
such as cardiovascular disease, 
cancer and neurodegenerative 
disease (15).  In a cross-sectional 
association study of 1,200 monocyte samples, we identified 1,794 age-associated methylation sites (16) 
and 2,704 age-associated transcripts (17), which were over-represented in two networks (autophagy and 
oxidative phosphorylation) and suggestive of decline in those functions with age. Both autophagy (18) 
and oxidative phosphorylation (19) are considered as key contributors to the aging process, and their 
dysfunctions have been linked to aging-related diseases (20;21). Changes in these aging-related omic 
biomarkers may be early indicators of cellular damage or disruption that eventually leads to age-related 
dysfunctions.  Assessment of these aging biomarkers in response to therapeutic intervention may also 
AMPK
PI3K
Akt
ACC
AMP
p66shc
IRS-1
IRS-2
Metformin
Rapamycin
Ras
Protein Synthesis
Autophagy
Stress Defense
Inflammation
Erk1/2
Healthspan and
Longevity
Resveratrol
NAD+
NADH
Cellular Survival
Cytokine
Receptor
ATP
SIRT1
mTOR
ATG13
p70S6K
4EBP1
Bax
p53
FOXO
1
2
3
NF-kB
Adiponectin
Receptor
INSR
IGF-1R
PAI-1
TNFa
IL-6
Adiponectin
Insulin
Metformin
IGF-1
Figure 1. Metformin targets multiple pathways of aging 


 
Protocol version: 9.4.18 
2 
provide molecular insight for personalizing treatment.  We propose a pilot study to examine changes in 
aging-related omic profiles after 3 months of metformin treatment in 35 monocyte samples from older 
adults using a randomized, double-blind, placebo-controlled crossover study design. 
 
Objectives 
Our overarching goal of the pilot study is to evaluate the utility of using the aging-related omic 
biomarkers as an indicator of pharmacologic responses in the anti-aging therapeutic intervention trials 
through the following specific aims.  Although this pilot study does not have sufficient power to 
definitively test all the aims, it will provide essential preliminary data for developing a full scale research 
program. 
• 
Aim 1A: To test the effects of the metformin treatment on transcriptomic profiles and related 
functional changes in human monocytes, 
• 
Aim 1B: To explore the effects of the metformin treatment on methylomic profiles in human 
monocytes, 
• 
Aim 2: To investigate the longitudinal relationship between transcriptional and functional 
changes in human monocytes during the metformin treatment and  
• 
Aim 3: To test the effects of the metformin treatment on frailty and other aging-related physical 
and cognitive measures and investigate the longitudinal relationship between these changes and 
transcriptional changes. 
 
Methods and Measures 
 
Design 
A randomized, double-blind, placebo-controlled crossover trial in 35 participants using metformin and 
matching placebo will be used. In the absence of a treatment by sequence interaction effect, this design 
can increase study power for evaluating treatment effects by allowing each participant to be his/her own 
control. The period effect may be minimum because the primary outcomes, methylation and 
transcriptional measures, are relatively stable overtime.  
 
Setting 
All visits will occur in the Geriatric Clinical Research Unit (G-CRU) or the Geriatric Research Center 
(GRC) in the Sticht Center on Aging. 
 
Subjects selection criteria 
All prospective participants in and around Forsyth County, NC will initially be screened via telephone to 
determine general eligibility. They will be asked about their age, medical history, and current 
medications. All participants must meet the inclusion/exclusion criteria below.   
Inclusion Criteria 
Age 65 – 79 
Must meet criteria from one or more of the following groups:  
 
 
      Group 1 (Can have 1 or 2 of these, but not all 3) 
• 
History of coronary artery disease  (MI/heart attack, stroke, heart failure, or peripheral 
artery disease) 
• 
Cancer, with no active treatment in the last year  
• 
MCI (MoCA >18<26 –inclusive of 1 point if <12 years of education 
 
 
      Group 2 
• 
Decline physical function (walking speed < 1 m/s) 
                   Group 3 (Either or both) 
• 
Abdominal obesity (>88cm women, >102cm men) AND hypertension (treated or resting   
 
blood pressure >140/90 


 
Protocol version: 9.4.18 
3 
• 
Abdominal obesity (>88cm women, >102cm men) AND hyperlipidemia (treated or   
 
fasting total cholesterol >240 
English literacy 
Willing to provide informed consent  
Exclusion Criteria 
 eGFR <45 
Type 2 diabetes (HbA1c>6.5) or type 1 diabetes 
Any tobacco or nicotine product use in the past year  
Low vitamin B12 Levels (< 300 pg/mL) 
Self-reported severe difficulty or inability to walk 400m or climb 10 steps (from Q 2 and 19 
on PAT-D) 
Self-reported difficulty or inability to perform basic ADL functions (from Q 10, 13, 14, 16 on 
PAT-D) 
Excessive alcohol use (>14 drinks/week) 
Cancer requiring treatment in past year (except skin) 
Dementia – diagnosed and/or MoCA score <18 
Parkinson’s or other neurological disease 
Chronic liver disease or cirrhosis 
End stage renal disease or on dialysis 
Rheumatic conditions (Rheumatoid arthritis, lupus, and any other autoimmune disease the PI 
deems them to be ineligible for) 
Thyroid problems the PI deems them to be ineligible for 
Recent or recurrent exacerbation of gout  
Involved in another interventional study 
Hemoglobin <8 or diagnosed with anemia 
Recent unintentional weight change (+/- 10 lbs. in the last 12 months) 
BMI <18.5 
Likely to not follow the protocol  
 
PI deems unfit to participate 
Already taking Metformin or any other drug intended to treat diabetes 
 
Screening, consent and randomization. Individuals who pass the telephone screening will be scheduled 
for a visit to the Geriatric Research Clinic (GRC) in the Sticht Center on Aging for a screening visit (SV). 
Before any data collection, all participants will provide written informed consent and complete a HIPAA 
authorization form in accordance with the Wake Forest School of Medicine Institutional Review Board 
policies. Individuals who meet all eligibility criteria and provide informed consent will be invited back for 
the first baseline visit (BV). At the end of BV, participants will be randomized to one of the two study 
intervention sequences (metformin followed by placebo or placebo followed by metformin) using a web-
based randomization scheme (developed by Dr. Miller). The randomization sequences will be unknown to 
the research staff. Intervention assignment will be generated using a program that the study coordinator 
will access from his/her PC through the study website.   
 
Schedule and organization of assessment visits 
All assessments will be conducted during 4 visits (before and after each intervention) according to the 
chart below. All examiners are trained in the standardized conduct of all assessments before data 
collection.  Participants will be instructed to wear appropriate and comfortable clothing, and standardized 
written instructions will be provided prior to each study visit. 
 
 
 
 


 
Protocol version: 9.4.18 
4 
 
Assessment timeline                                               Visit code 
SV 
BV 
On 
trial 
Mid 
 
On 
trial 
 
FV 
Activity/assessment                                                       Week number 
-4 
0 
12-14 
24-26 
Informed consent, review inclusion/exclusion criteria, demographics, 
weight, height, BP and pulse, fasting screening blood draw (metabolic 
blood panel, lipid panel, CBC, Vit B12, Hba1c), eSPPB, cognitive 
screen (MoCA), waist circumference,  medical history, medications 
PAT-D,  
X 
 
 
 
 
 
Blood collection for methylomic and transcriptomic, bioenergetic 
capacity, CBC, and blood for storage, DSST, leg press, grip, , MATsf, 
and 6MWD  
 
X 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Crossover – Dispense New Medication 
 
 
 
X 
 
 
Vitals, blood collection for methylomic and transcriptomic, bioenergetic 
capacity, and blood for storage, CBC, CMP, lipids, Hba1c,  eSPPB, 
MoCA, DSST, leg press, grip, PAT-D, MAT-sf, 6MWD 
 
 
 
X 
 
X 
Health Maintenance  
 
 
 
 
 
X 
The screening visit (SV) will be conducted in the morning following an 8-hour fast for measurement of 
lipids, blood count, Hba1c, Vitamin B12, and a metabolic panel for screening purposes. Vitals (blood 
pressure, pulse, height, weight, and waist circumference) are collected and the blood draw completed, 
participants will be given a snack and continue with the remainder of the visit. First, the expanded short 
physical performance battery (eSPPB) will be administered and scored and then undergo a cognitive 
screen, assessed using the Montreal Cognitive Assessment (MoCA), and a medical history, review of 
medications and dietary supplements We will also ask about the participants demographics and physical 
abilities using the Pepper Assessment Tool for Disability (PAT-D), 
 
The first baseline visit (BV), will be conducted in the morning following an 8-hour fast for blood 
collection for methylomic and transcriptomic measures, bioenergetic capacity, CBC, as well as blood for 
storage. After these measures are complete, participants will be given a snack and will continue with the 
rest of the visit consisting of lower extremity muscle power (Nottingham Power Rig), grip strength, 6 
minute walk distance test (6MWD), and the Mobility Assessment Tool – short form (MAT-sf).  Cognitive 
function will be assessed using the Digit Symbol Test (DSST). Once the visit is complete, the participant 
will be randomized and placed in one of the following groups discussed below. Participants will be 
provided with an information sheet that will provide additional details on how and when to take the 
medication, who to call if they have any problems, possible side effects, and what to do should they 
encounter any side effects.  
 
Interventions and Interactions 
Eligible participants will receive both interventions (3-month metformin treatment and 3-month placebo). 
Randomization will be used to determine the order in which the participants receive each intervention 
(i.e., 15 participants with metformin treatment followed by placebo, and 15 with placebo followed by 
metformin treatment). Neither the participants nor the investigators know the intervention order of a 
participant. Metformin reaches peak plasma concentration within one to eight hours, has an average 
elimination half-life of 6.2 hours in plasma, and is cleared but not metabolized from the body by tubular 
secretion.  Treatment with metformin and placebo will be initiated at a dose of 425 mg taken orally once a 
day at night for 7 days. After the week, the participant will be called to assess tolerance and will be asked 
to increase dose to one pill at night at a dose of 850 mg for one week. At the end of the second week, 
participants will be called again and if they tolerated the second dose, they will be asked to take two 
850mg pills, one in the morning and one at night, for a total dose of 1700 mg which is within the range of 
the usual effective dose of 1500 to 2000 mg/day for the remainder of the 3 months.  This dosing regimen 
was created in order to avoid or reduce possible gastrointestinal side effects. This can be modified if the 


 
Protocol version: 9.4.18 
5 
participant is experiencing any side effects and will be handled on a case by case basis. Each study visit 
where stored blood is obtained (BV, Mid, FV) may be rescheduled if the subject has a fever, infection, or 
has taken antibiotics within 24hrs of this scheduled visit. 
 
All baseline assessments will be completed again at 12 weeks and again at 24 weeks as listed in the 
assessment table.  
 
Outcome Measure(s) 
The primary outcomes will be the eigengene scores (and related individual transcriptional measures) for 
the two transcriptional networks, the autophagy and oxidative phosphorylation.  The eigengene score is 
defined as the first principal component of a transcriptional network. The secondary outcomes will 
include functional, methylation and other aging-related measures.  
 
Individual methylation sites and transcripts, especially the eigengenes of autophage, oxidative 
phosphorylation and protein synthesis networks Methylomic and transcriptomic profiles in monocytes 
will be quantified using the Illumina HumanMethylation450 BeadChip and the Illumina HumanHT-12 v4 
Expression BeadChips, respectively, at Dr. Liu’s laboratory (22).  Blood will be collected in Vacutainer 
CPTTM cell separation tubes containing sodium citrate (Becton Dickinson, Rutherford, NJ) to separate 
peripheral blood mononuclear cells.  Then, monocytes will be isolated with the anti-CD14 coated 
magnetic beads using AutoMACs automated magnetic separation unit (Miltenyi Biotec, Bergisch 
Gladbach, Germanry). DNA and RNA will be isolated simultaneously using the AllPrep DNA/RNA Mini 
Kit (Qiagen, Inc., Hilden, Germany).  
 
Functional measures: An autophagic profile in monocytes including macroautophagy, microautophagy 
and chaperone-mediated autophagy will be measured using fluorescent reporters at Dr. Ana Maria 
Cuervo’s lab in Albert Einstein College of Medicine. 
 
Mitochondrial Function: Respirometric profiling will be used to assess bioenergetic capacity, 
respiratory control and electron transport chain function at Dr. Molina’s lab (23). This will be performed 
by examining the oxygen consumption profile of blood monocytes. Specific outcomes of mitochondria 
function include respiratory control ratio (RCR), state 3 (maximal oxygen consumption rate), and state 4 
(oxygen consumption upon inhibition of ATP synthase). 
 
Other Data 
 
Vital Signs Prior to randomization data are collected on sitting blood pressure, heart rate, and weight. 
Body height is measured once prior to randomization. The blood pressure assessments will allow the 
determination of the incidence of hypertension and serve as basis for a temporary exclusion. The other 
measures are collected primarily for descriptive purposes. 
 
Demographics and co-morbidities: Medical information regarding co-morbidities and medications will 
be ascertained at the screening visit.  Demographic data such as socio-economic status, education level, 
age, and race also will be recorded and used as covariates if necessary. Information about preventative 
health screenings and other health maintenance information is asked at the follow up visit. 
 
Physical performance will be assessed using the expanded Short Physical Performance Battery (SPPB) 
(24). The expanded SPPB consists of 5 repeated chair stands, standing balance (semi- and full-tandem 
stands and a single leg stand for 30 seconds), a 4-m walk to assess usual gait speed, and a narrow 4-m 
walk test of balance (walking at usual pace within lines of tape spaced 20 cm apart). Scores for the 
traditional 0-12 point SPPB can also be obtained from these tests. We will also assess physical 


 
Protocol version: 9.4.18 
6 
performance using the six minute walk distance test (6MWD). The participant is asked to walk at a pace 
they can maintain for six minutes and the distance covered will be recorded.  
Lower extremity muscle power will be measured using the Nottingham Power Rig, a safe, convenient 
method for assessing power output from the lower limb which has been used reliably in older adults. (25) 
Participants will sit in a chair and unilaterally depress a foot lever attached to a flywheel as hard and as 
fast as they can. Power output, derived from the acceleration of the flywheel, will be recorded in Watts. 
Power will be averaged for each leg following five trials at maximal effort. Participants that have had a 
unilateral hip or knee replacement should not have that side tested.  
 
Grip strength will be measured twice in each hand to the nearest 2 kg using an isometric Hydraulic Hand 
Dynamometer (Jamar, Bolingbrook, IL) and the mean value from the stronger hand used. Participants will 
be excluded from performing the test if they report hand-pain or recent hand or wrist surgery.   
 
Cognitive function will be assessed during screening using the Montreal Cognitive Assessment (MoCA) 
(26), participants must score ≥18 to be eligible. We will also assess psychomotor speed, attention, and 
working memory using the Digit Symbol Substitution Test (DSST) (27; 28). Participants are given a 
series of numbered symbols and then asked to draw the appropriate symbols below a list of random 
numbers. The score is the number of correctly made matches in 2 minutes (120 seconds).  
 
Body composition will be measured by circumference measurements of the waist which is made with a 
tape measure.   
 
Blood lipids (total cholesterol, HDL-Cholesterol, Triglycerides and calculated LDL levels) will be 
measured at a clinical lab and all results will be entered into the data system. 
 
Activities of daily living will be assessed using the Mobility Assessment Tool – Short Form (MAT-sf). 
This is a novel, computerized tool for self-assessment of functional performance designed to reduce bias 
from factors such as age, gender and body image. The Pepper Assessment Tool for Disability (PAT-D) 
will also be used to assess the participant’s ability to complete an array of important day-to-day activities 
without difficulty and, for a subset of activities, without personal assistance. 
 
Medication adherence: Although we will attempt to enhance adherence by monthly calls to participants, 
there may be inter-individual variability in adherence to the medication. At the end of each phase, 
participants will be asked to return any unused pills for a pill count to determine participant adherence. 
Our primary analyses will be an intent-to-treat analysis of the effects of the metformin intervention, but 
secondary analyses will include adherence as a covariate. 
 
Analytical Plan  
We will use an analysis of variance model for crossover design to assess the effect of metformin on 
transcriptional profiles and other aging-related outcomes. The factors in the analysis will include the 
baseline measure, sequence, participant within sequence, period, and metformin treatment. We will 
explore for the metformin by sequence interaction and will base estimates of the metformin effect on 
whether this interaction effect is significant.  We will also perform exploratory, linear regression analysis 
with transcriptional changes as the explanatory variables and changes in other aging-related measures as 
the outcome variables. The analysis will be focused on the eigengene scores of the autophagy and 
oxidative phosphorylation transcriptional networks (and related individual transcriptional measures).  As 
this is a pilot study, focus of analyses will be on estimation of effects and constructing appropriate 95% 
confidence intervals for these effects.   
 
 
Human Subjects Protection 


 
Protocol version: 9.4.18 
7 
 
Risk to participants 
The Diabetes Prevention Program (DPP) study, a placebo-controlled study of metformin vs. lifestyle 
intervention in persons with pre-diabetes (included subjects with fasting blood glucose 90-125 mg/dL, n = 
3,234) provides insight into side effects of long-term metformin administration in the elderly and non-
diabetics.29 Of note, the most common side effect was not hypoglycemia, but gastrointestinal symptoms 
(see table below). 
 
 
  
As far as common side effects, GI side effect and diarrhea are transient and usually pass after a week of 
therapy. In the DPP study, 3-5% of subjects had continuous diarrhea; this portion of subjects would be 
excluded in the present trial during the run-in, dose-titration period. No one had metformin associated 
lactic acidosis. Hypoglycemic events were either not in evidence or reported. 
 
Weight loss is a common occurrence with metformin and will be monitored. In such a case some patients 
may complain of hypoglycemic symptoms (rapid heartbeat, feeling light-headed or fainting, and nausea), 
and in this case subjects will be asked to refrain from taking their next dose. Subjects may not need 
medical interventions, but will be given instruction for fruit juice or other carbohydrate and to call the 
coordinator immediately to come in for a blood glucose check. Levels will be checked by finger 
(Accucheck) and labs to LabCorp to confirm levels.  If blood glucose levels are < 60 mg/dL they will be 
removed from the study and replaced by an additional participant. No more side effects were noted in the 
elderly; in fact, they had a better adherence to therapy.  Young and elderly had the same rates of GI side 
effects and diarrhea. 
 
Subject Recruitment Methods 
We will recruit these individuals using community-based recruitment strategies including newspaper ads 
and mass mailings. We will also advertise in the VITAL newsletter (BG99-559) and participate in 
community outreach events. 
 
Informed Consent 
Written informed consent will be obtained from each subject. The informed consent process will follow 


 
Protocol version: 9.4.18 
8 
the procedures of the WFSM Institutional Review Board. The study interviewers will explain the purpose, 
methods and extent of the study to prospective participants. The potential participant is asked to read the 
informed consent form and ask questions. The form is written in simple easy to understand language. We 
require study staff to review all of the key aspects of the study verbally with the potential participants. 
Staff is provided with a structured checklist for this purpose. Staff is then required to question potential 
participants to ascertain whether s/he has understood the information. Potential participants who are 
illiterate or have impaired vision must have the consent read to them, followed by review of the checklist, 
opportunity for questions, and discussion. This process will take place in a quiet, private room. A copy of 
the signed and dated consent form will be given to participants, and the original document will be placed 
in subjects’ individual study files, which will be stored in a secure location. In compliance with the Health 
Insurance Portability and Accountability Act (HIPAA) and the Standards for Privacy of Individually 
Identifiable Health Information of the Department of Health and Human Services, we will access personal 
health information only after obtaining informed consent. 
 
Confidentiality and Privacy 
All data are obtained for research purposes only. Confidentiality of data is maintained by using research 
identification numbers which uniquely identify each individual. Data will be used only in aggregate and 
no identifying characteristics of individuals will be published or presented. The information collected has 
a low potential for abuse because the data do not address sensitive issues. Nevertheless, appropriate 
measures are taken to prevent unauthorized use of study information. Research records are kept in a 
locked room. Data access will be limited to study staff. Information linking IDs to individuals is kept on a 
secure, password-protected server to which only authorized study personnel will have access. Data and 
records will be kept locked and secured, with any computer data password protected. A web-based data 
entry system will be created for this study which will allow access only to study staff (user id and 
password required to access). Blinded staff will not have access to blinded study information on the web-
based database. Computer files are stored on file servers, which are backed up each night and stored for 
easy retrieval in case of emergency.  Files may not be obtained from the research unit by persons other 
than the research personnel, who are asked to sign a document agreeing to maintain the confidentiality of 
the information. No data files distributed for analysis will include personal information. No reference to 
any individual participant will appear in reports, presentations, or publications that may arise from the 
study. After the study is completed, the data will be stored with other completed research studies in a 
locked secure area. 
 
Data and Safety Monitoring 
The principal investigator along with the study physician (William Applegate) will be responsible for the 
overall monitoring of the data and safety of study participants. The study physician will be unmasked to 
treatment assignment as needed and appropriate. The principal investigator will also be assisted by other 
members of the study staff. All participants will have a protocol-driven medical monitoring plan to 
consistently assess for adverse events or medical safety concerns. In addition, participant safety in all 
Wake Forest Pepper Center OAIC-supported studies is monitored by a Data and Safety Monitoring 
Committee (DSMC). It reviews study recruitment, drop-outs, protocol changes, losses to follow-up, and 
adverse events every 6 months. The DSMC has authority to recommend changing or stopping the 
protocol. In the latter case, the PI will immediately act upon the recommendation according to 
institutional policy and in consultation with the Wake Forest Pepper Center OAIC Executive Committee. 
 
Reporting of Unanticipated Problems, Adverse Events or Deviations 
Any unanticipated problems, serious and unexpected adverse events, deviations or protocol changes will 
be promptly reported by the principal investigator or designated member of the research team to the IRB 
and sponsor. 
 
 


 
Protocol version: 9.4.18 
9 
Use of biological samples by other investigators 
Biological samples may be used by investigators other than the investigators of the current study. The use 
will be limited to non-commercial purposes. The names and other personal identifiers of the study 
participants will not be sent to any recipients of the blood samples. 
 
Storage and disposal of biological material 
Blood samples will be stored at Wake Forest University Medical Center for up to twenty years after the 
end of the trial at which time the samples will be destroyed. Biological specimens will be stored in locked 
-70oC alarmed freezers located in a locked room. The lab coordinator and the PIs have access to the keys 
of the freezers. All the specimens will have numerical study IDs with no personal identifiers of the 
participants. These are stored under the Pepper Center Tissue Repository (IRB#1219). 
 
Reference List 
 
 1.  Harrison,DE, Strong,R, Allison,DB, Ames,BN, Astle,CM, Atamna,H, Fernandez,E, Flurkey,K, 
Javors,MA, Nadon,NL, Nelson,JF, Pletcher,S, Simpkins,JW, Smith,D, Wilkinson,JE, Miller,RA: 
Acarbose, 17-alpha-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in 
males. Aging Cell 13:273-282, 2014 
 2.  Martin-Montalvo,A, Mercken,EM, Mitchell,SJ, Palacios,HH, Mote,PL, Scheibye-Knudsen,M, 
Gomes,AP, Ward,TM, Minor,RK, Blouin,MJ, Schwab,M, Pollak,M, Zhang,Y, Yu,Y, Becker,KG, 
Bohr,VA, Ingram,DK, Sinclair,DA, Wolf,NS, Spindler,SR, Bernier,M, de,CR: Metformin improves 
healthspan and lifespan in mice. Nat Commun 4:2192, 2013 
 3.  Miller,RA, Harrison,DE, Astle,CM, Baur,JA, Boyd,AR, de,CR, Fernandez,E, Flurkey,K, 
Javors,MA, Nelson,JF, Orihuela,CJ, Pletcher,S, Sharp,ZD, Sinclair,D, Starnes,JW, Wilkinson,JE, 
Nadon,NL, Strong,R: Rapamycin, but not resveratrol or simvastatin, extends life span of genetically 
heterogeneous mice. J Gerontol A Biol Sci Med Sci 66:191-201, 2011 
 4.  Satoh,A, Brace,CS, Rensing,N, Cliften,P, Wozniak,DF, Herzog,ED, Yamada,KA, Imai,S: Sirt1 
extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH 
and LH. Cell Metab 18:416-430, 2013 
 5.  Knowler,WC, Barrett-Connor,E, Fowler,SE, Hamman,RF, Lachin,JM, Walker,EA, Nathan,DM: 
Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J 
Med 346:393-403, 2002 
 6.  Kirpichnikov,D, McFarlane,SI, Sowers,JR: Metformin: an update. Ann Intern Med 137:25-33, 2002 
 7.  Bailey,CJ, Turner,RC: Metformin. N Engl J Med 334:574-579, 1996 
 8.  Collier,CA, Bruce,CR, Smith,AC, Lopaschuk,G, Dyck,DJ: Metformin counters the insulin-induced 
suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal 
muscle. Am J Physiol Endocrinol Metab 291:E182-E189, 2006 


 
Protocol version: 9.4.18 
10 
 9.  Fantus,IG, Brosseau,R: Mechanism of action of metformin: insulin receptor and postreceptor 
effects in vitro and in vivo. J Clin Endocrinol Metab 63:898-905, 1986 
 10.  Madiraju,AK, Erion,DM, Rahimi,Y, Zhang,XM, Braddock,DT, Albright,RA, Prigaro,BJ, Wood,JL, 
Bhanot,S, MacDonald,MJ, Jurczak,MJ, Camporez,JP, Lee,HY, Cline,GW, Samuel,VT, Kibbey,RG, 
Shulman,GI: Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate 
dehydrogenase. Nature 510:542-546, 2014 
 11.  Rena,G, Pearson,ER, Sakamoto,K: Molecular mechanism of action of metformin: old or new 
insights? Diabetologia 56:1898-1906, 2013 
 12.   Effect of intensive blood-glucose control with metformin on complications in overweight patients 
with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 
352:854-865, 1998 
 13.  Libby,G, Donnelly,LA, Donnan,PT, Alessi,DR, Morris,AD, Evans,JM: New users of metformin are 
at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 
32:1620-1625, 2009 
 14.  Ng,TP, Feng,L, Yap,KB, Lee,TS, Tan,CH, Winblad,B: Long-term metformin usage and cognitive 
function among older adults with diabetes. J Alzheimers Dis 41:61-68, 2014 
 15.  Karlmark,KR, Tacke,F, Dunay,IR: Monocytes in health and disease - Minireview. Eur J Microbiol 
Immunol (Bp) 2:97-102, 2012 
 16.  Reynolds,LM, Taylor,JR, Ding,J, Lohman,K, Johnson,C, Siscovick,D, Burke,G, Post,W, Shea,S, 
Jacobs,DR, Jr., Stunnenberg,H, Kritchevsky,SB, Hoeschele,I, McCall,CE, Herrington,DM, 
Tracy,RP, Liu,Y: Age-related variations in the methylome associated with gene expression in 
human monocytes and T cells. Nat Commun 5:5366, 2014 
 17.  Reynolds,LM, Ding,J, Taylor,JR, Lohman,K, Soranzo,N, de la Fuente,A, Liu,TF, Johnson,C, 
Barr,RG, Register,TC, Donohue,KM, Talor,MV, Cihakova,D, Gu,C, Divers,J, Siscovick,D, 
Burke,G, Post,W, Shea,S, Jacobs,DR, Jr., Hoeschele,I, McCall,CE, Kritchevsky,SB, Herrington,D, 
Tracy,RP, Liu,Y: Transcriptomic profiles of aging in purified human immune cells. BMC Genomics 
16:333, 2015 
 18.  Rubinsztein,DC, Marino,G, Kroemer,G: Autophagy and aging. Cell 146:682-695, 2011 
 19.  Lopez-Otin,C, Blasco,MA, Partridge,L, Serrano,M, Kroemer,G: The hallmarks of aging. Cell 
153:1194-1217, 2013 


 
Protocol version: 9.4.18 
11 
 20.  Choi,AM, Ryter,SW, Levine,B: Autophagy in human health and disease. N Engl J Med 368:651-
662, 2013 
 21.  Lin,MT, Beal,MF: Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. 
Nature 443:787-795, 2006 
 22.  Liu,Y, Ding,J, Reynolds,LM, Lohman,K, Register,TC, de la Fuente,A, Howard,TD, Hawkins,GA, 
Cui,W, Morris,J, Smith,SG, Barr,RG, Kaufman,JD, Burke,GL, Post,W, Shea,S, McCall,CE, 
Siscovick,D, Jacobs,DR, Jr., Tracy,RP, Herrington,DM, Hoeschele,I: Methylomics of gene 
expression in human monocytes. Hum Mol Genet 22:5065-5074, 2013 
 23.  Tyrrell,DJ, Bharadwaj,MS, Van Horn,CG, Kritchevsky,SB, Nicklas,BJ, Molina,AJ: Respirometric 
Profiling of Muscle Mitochondria and Blood Cells Are Associated With Differences in Gait Speed 
Among Community-Dwelling Older Adults. J Gerontol A Biol Sci Med Sci 2014 
 
24.     Simonsick EM, Newman AB, Nevitt MC, Kritchevsky SB, Ferrucci L, Guralnik JM, Harris T. 
Measuring higher level physical function in well-functioning older adults: expanding familiar 
approaches in the Health ABC study. J Gerontol A Biol Sci Med Sci 2001;56(10):M644-M649. 
 
25.    Bassey EJ, Short AH. A new method for measuring power output in a single leg extension: 
feasibility, reliability and validity. Eur J Appl Physiol Occup Physiol 1990;60(5):385-90.  
 
26.    Donoghue OA, Horgan NF, Savva GM, Cronin H, O'Regan C, Kenny RA. Association between 
timed up-and-go and memory, executive function, and processing speed. J Am Geriatr Soc. 2012 
Sep;60(9):1681-6. 
 
27.    Wechsler D. WAIS-R manual. New York: Psychological Corporation; 1981. 
 
28.  Salthouse TA. The role of memory in the age decline in digit-symbol substitution performance. J 
Gerontol 1978 March;33(2):232-8.   
 
29.  Knowler et al. Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or              
Metformin. N Engl J Med 346(6): 393-403, 2002 
 

ICF_001.pdf: 
Title: Genomic Outcomes of Metformin
NCT02986659
Date:  9/26/18


Page 1 of 12
Version 9.4.18
Section on Gerontology and Geriatric Medicine
GENOMIC OUTCOMES OF METFORMIN (GO MET)
Informed Consent Form to Participate in Research
Jingzhong Ding, MD, PhD, Principal Investigator
INTRODUCTION
You are invited to be in a research study. Research studies are designed to gain scientific 
knowledge that may help other people in the future. You are being asked to take part in this 
study because you are 65-79 years old and have expressed interest in the study. Your 
participation is voluntary. Please take your time in making your decision as to whether or not 
you wish to participate. Ask your study doctor or the study staff to explain any words or 
information contained in this informed consent document that you do not understand. You may 
also discuss the study with your friends and family.
WHY IS THIS STUDY BEING DONE?
Medical scientists have found that people with diabetes who take the drug Metformin have less 
age-related disease than those taking other treatments and researchers believe it may prevent 
numerous diseases and conditions that effect older people. In addition, metformin extends 
lifespan in some animal models of human disease. The purpose of this study is to see if taking 
Metformin causes changes in blood cells consistent with improved health and longevity in 
people who do not have diabetes.  In this study Metformin will be compared to placebo. A 
placebo is a substance, like a sugar pill, that is not thought to have any effect on your disease or 
condition. In this study you will either receive the active study medication, Metformin or placebo 
which is not active. Placebos are used in research studies to see if the drug being studied really 
does have an effect. 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
A total of 35 people at Wake Forest Baptist Medical Center will take part in this study. In order 
to identify the 35 subjects needed, we may need to screen as many as 110 because some people 
will not qualify to be included in the study.
WHAT IS INVOLVED IN THE STUDY?
If you agree to participate in this study by signing this consent form, you will be asked to 
complete a screening visit to see if you qualify for the study. You will then complete a baseline 
visit before beginning the intervention. The details about all study visits and procedures are 
provided below. We will make every effort to follow the visit procedures in the order they are 
outlined below; however, it may be necessary at times to make changes to accommodate 
different schedules.
Screening Visit (SV)
We will ask that you come to the Sticht Center having fasted for at least 8 hours prior to your 
appointment time, with nothing to eat or drink except water.  You will learn all the details of the 
study and you will be given time to ask any questions and get satisfactory answers.  Then, you 
will be asked to sign this informed consent form if you qualify for the study.  After signing the 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00034977
Meeting Date Approved 9/26/2018          
Version Valid Until: 1/1/2019


Page 2 of 12
Version 9.4.18
consent form, we will: 

Draw blood (approximately 1 tablespoon) from a vein in your arm to collect
measurement of lipids (cholesterol), blood counts and chemistries, average blood sugar
levels, Vitamin B12, and liver and kidney function for screening purposes

Provide you with a light snack

Measure your blood pressure, pulse, height, weight, and waist circumference

Ask you to do a series of physical performance tests including balance tests, chair rise
(stand up from a seated position in a chair 5 times), short walk test (4 meters) and a
narrow walk test

Ask you questions about your memory

Ask you questions about your background, medical history, difficulty doing different
physical tasks , and review of medications and dietary supplements
This visit will take approximately 1 – 1 ½ hours to complete.  We will call you within a week to 
let you know if you qualify to continue for a Baseline Visit.  If you do not qualify we will send 
you a letter with the results of your lab work so that you many share with your doctor, if you 
would like.
Baseline Visit (BV)
Approximately one week later you will come to the Sticht Center having fasted for at least 8 
hours prior with nothing to eat or drink except water. We ask that if you have a fever, infection, 
or have been taking antibiotics within 24hrs of this scheduled visit that you let us know so we 
can reschedule your visit. We will: 

Draw blood (approximately 5 tablespoons) to measure your cells response to Metformin
and ability to make energy, to measure your blood counts and chemistries, as well as
blood for storage.

Provide you a light snack

Ask you to do a series of physical performance test that include testing your leg strength
on chair-like devices, testing your grip strength with a handheld device, asking you to
perform a 6 minute walking test

Have you watch short video clips of different physical tasks and answer questions related
to the video clips.

Ask you questions about your memory

Once the visit is complete, you will be randomized and placed in one of the following
groups discussed below
This visit will take approximately 2- 2 ½ hours to complete.
You will be randomized into one of the two study groups described below. Randomization 
means that you are put into a group by chance. It is like flipping a coin. You will have an equal 
chance of being placed in either group.
The groups are:
3 months of Metformin then switching to 3 months of placebo
3 months of placebo then switching to 3 months of Metformin
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00034977
Meeting Date Approved 9/26/2018          
Version Valid Until: 1/1/2019


Page 3 of 12
Version 9.4.18
Eligible participants will receive both interventions (3-month metformin treatment and 3-month 
placebo). Neither you nor the study staff will know which group you will be assigned to. All 
participants will have the same dose schedule as detailed below.
You will start by swallowing a pill (at a dose of 425 mg or placebo) once a day with dinner for 7 
days. After the week, a study staff member will call you to see how it’s going and you will be 
asked to increase dose to one pill with dinner (at a dose of 850 mg or placebo - from a different 
bottle) for one week. At the end of the second week, you will be called again and if things are 
going okay, you will be asked to take two (850mg) pills, one in the morning and one at night, 
(for a total dose of 1700 mg or placebo) for the remainder of the 3 months until you return for 
your midpoint visit.  
Once you are randomized to the study drug you will be provided a Participant Guidelines form 
that will give you details on how to take your pills and what to do if you have a reaction while 
taking them.  This form will include your study coordinator’s contact information and then name 
of the study physician if you need to call with questions or concerns.  
Midpoint Visit (MID)
After being in the study for 12 weeks we will call to schedule you to return to the Sticht Center 
having fasted for at least 8 hours prior to your appointment time, with nothing to eat or drink 
except water.  We ask that if you have a fever, infection, or have been taking antibiotics within 
24hrs of this scheduled visit that you let us know so we can reschedule your visit. At this visit we 
will: 

Measure your blood pressure, pulse, height, weight, and waist circumference)

Draw blood (approximately 6 tablespoons) to measure your cells response to Metformin
and ability to make energy as well as blood for storage.
We will also test your liver and kidney function, your blood counts and chemistries, your
average blood sugar level, and your lipids (cholesterol).

Ask you to do a series of physical performance test that include testing your leg strength
on chair-like devices, testing your grip strength with a handheld device, asking you to
perform a 6 minute walking test

Ask you to do a series of physical performance tests including balance tests, chair rise
(stand up from a seated position in a chair 5 times), short walk test (4 meters) and a
narrow walk test

As you to answer some questions on how much difficulty you have doing different
physical tasks and have you watch short video clips of different physical tasks and
answer questions related to the video clips.

Ask you questions about your memory
This visit will take approximately 2- 2 ½ hours to complete.  When you return for this visit we 
will ask that you bring in all your remaining pills and the study staff will then dispense your new 
pills to take for the remainder of time you are in the study.  You will be given the same amount 
of pills as you did at your baseline visit and instructed to take each amount the same as in the 
beginning of the study with taking a pill (at a dose of 425 mg or placebo) taken orally once a day 
with dinner for 7 days. After the week, a study staff member will call you to see how it is going 
and you will be asked to increase dose to one pill with dinner (at a dose of 850 mg or placebo - 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00034977
Meeting Date Approved 9/26/2018          
Version Valid Until: 1/1/2019


Page 4 of 12
Version 9.4.18
from a different bottle) for one week. At the end of the second week, you will be called again 
and if things are going well, you will be asked to take two (850mg or placebo) pills, one in the 
morning and one at night, (for a total dose of 1700 mg or placebo) for the remainder of the 3 
months until you come in for your last visit. 
Follow up Visit (FV)
After another 12 weeks we will call to schedule you to return to the Sticht Center having fasted 
for at least 8 hours prior to your appointment time, with nothing to eat or drink except water. We 
ask that if you have a fever, infection, or have been taking antibiotics within 24hrs of this 
scheduled visit that you let us know so we can reschedule your visit.  At this visit we will: 

Measure your blood pressure, pulse, height, weight, and waist circumference)

Draw blood (approximately 6 tablespoons) to measure your cells response to Metformin
and ability to make energy as well as blood for storage.

We will also test your liver and kidney function, your blood counts and chemistries, your
average blood sugar level, and your lipids (cholesterol).

Ask you to do a series of physical performance test that include testing your leg strength
on chair-like devices, testing your grip strength with a handheld device, asking you to
perform a 6 minute walking test

Ask you to do a series of physical performance tests including balance tests, chair rise
(stand up from a seated position in a chair 5 times), short walk test (4 meters) and a
narrow walk test

As you to answer some questions on how much difficulty you have doing different
physical tasks and have you watch short video clips of different physical tasks and
answer questions related to the video clips.

Ask you questions about your memory

Ask you about types of preventative screenings and immunizations you may have
received and if you regularly exercise.
This visit will take approximately 2- 2 ½ hours to complete.  When you return for this visit we 
will ask that you bring in all your remaining pills.
You will have blood withdrawn from a vein at a total of 4 study visits. The total amount of blood 
withdrawn during the study will be approximately (18 tablespoons).
We can send copies of your test results to your personal physician. Even if you do not wish to 
have any of your medical information sent to your physician, you can still participate in this 
research study.  These results include copies of the clinical labs in which the results are received 
by the study the day after each visit in which blood is drawn. 
Do you request that we send important medical findings from your study tests/exams to your 
personal physician? 
[   ] Yes
[   ] No
___________ Initials
As part of this study, blood samples will be obtained and DNA from your blood sample will be 
purified. DNA, or deoxyribonucleic acid is the substance in your cells that stores and transmits 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00034977
Meeting Date Approved 9/26/2018          
Version Valid Until: 1/1/2019


Page 5 of 12
Version 9.4.18
inherited traits, such as eye color or blood type.  Because we do not know how the results of this 
DNA study relate to your individual health, the results of the research will not be given to you or 
your doctor.  These results will not be placed in your medical records.
Storage of Biological Blood
If you agree to participate in this study, we will draw 4 tablespoons of blood to use for future 
research. This sample will be kept and may be used in future research to learn more about health 
and disease.  Your sample will be obtained in the Geriatrics Clinical Research Unit at Wake 
Forest University Baptist Medical Center. The sample will be stored in the Geriatrics Laboratory 
and it will be given only to researchers approved by Dr. Jingzhong Ding.  An Institutional 
Review Board (IRB) must also approve any future research study using your blood sample. In 
order to participate in this study, you must be willing to provide this sample for future research. 
Your blood sample will be stored with a unique identifier and will not include any identifiable 
information about you such as your name, address, telephone number, social security number, 
medical record number or any of the identifiers outlined in the HIPAA Privacy Rule. The unique 
identifier will be a randomly assigned number and only the principal investigator will have 
access to the code that links the unique identifier to you. Your name, address, social security 
number, etc., will never be disclosed to future researchers and neither will the code that links 
your identifiers to the sample.
The research that may be performed with your blood sample is not designed to help you 
specifically. There is no personal benefit to you from taking part in this aspect of the research 
study. It might help people who have diseases at some point in the future, but it is not known if 
this will happen. The results of the research performed with your blood will not be given to you 
or your doctor. The results will not be put in your medical record. The research using your blood 
sample will not affect your care.
Your blood sample will be used only for research and will not be sold. The findings from this 
research may result in the future development of products that are of commercial value. There 
are no plans to share any of the profits with you which may occur as a result of the research.
HOW LONG WILL I BE IN THE STUDY?
You will be in the study for about 24 weeks or 6 months. You can stop participating at any time. 
If you decide to stop participating in the study we encourage you to talk to the investigators or 
study staff first to learn about any potential health or safety consequences. Before having surgery 
or any X-ray/scanning procedure using injectable iodinated contrast material, tell your doctor 
that you are taking Metformin. You will need to temporarily stop this medication before the time 
of your surgery/procedure. Consult your doctor for further instructions.
WHAT ARE THE RISKS OF THE STUDY?
Being in this study involves some risk to you. You should discuss the risk of being in this study 
with the study staff. Risks and side effects related to the procedures and drug we are studying 
may include:
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00034977
Meeting Date Approved 9/26/2018          
Version Valid Until: 1/1/2019


Page 6 of 12
Version 9.4.18
1. Study Medications
Metformin is a widely used medication. Common side effects include nausea, gas, vomiting, 
stomach upset, diarrhea, weakness, or a metallic taste in the mouth may occur. These often go 
away after a short time. If any of these effects persist or worsen, please tell us immediately.  If 
stomach symptoms return later (after taking the same dose for several days or weeks), tell the 
study staff immediately. Limit alcohol while using this medication. Participants may see a drop 
in blood sugar from taking the Metformin. However, Metformin has been used with thousands 
without diabetes and shown no major concerns. The study staff and study physicians will be 
monitoring all participants to avoid any issues.  Side effects of low blood sugar include rapid 
heartbeat, fatigue, headache, hunger. If you do experience these effects after taking the 
medication, we ask you tell us immediately.  We will provide randomized participants with exact 
details once they are in the study on how to handle any situation that may occur in their 
Participant Guideline form. There are no known side effects of taking a placebo. There is no risk 
of additional side effects by starting in one group or the other and then switching to the other 
group. Both groups will start with a low dose and gradually work your way up to a full dose to 
minimize any side effects. 
2. Physical function tests
Your ability to perform certain physical activities will be measured before and after the 
intervention.  There is a slight risk of falls while participating in the balance test.  However, you 
will be positioned beside a step or wall that can be reached immediately if you feel that you are 
going to lose your balance.  Additionally, the person conducting the test will stand next to you at 
all times.  You may have slight hand or leg discomfort during the grip and leg strength tests, but 
this usually stops once the tests are over.  There is a small possibility that you may stumble, fall 
or aggravate one of your joints/muscles during the walking test or knee strength test. 
3. Blood Sampling
You may experience discomfort, bruising and/or bleeding where the needle is inserted.  
Occasionally, some people become dizzy, lightheaded or feel faint. Infection may occur on rare 
occasions.  Frequent donation of blood can result in low iron in your blood (iron deficient 
anemia).  You should not donate blood for at least 8 weeks after completing this study.
4. Body measurements
Several methods will be used to determine the amount of fat, muscle and bone and the location 
of body fat.  A tape measure will be used to measure the size of your waist.  
5. Questionnaires
During the clinic visits we will ask you a variety of questions that you may feel are boring or 
wonder why we need this information. Please know that we only collect information that we feel 
may be useful to know when studying the effects of Metformin. You may become tired during 
the questionnaires or memory testing and if this occurs, we can take a break until you are ready 
to continue. 
There also may be other side effects that we cannot predict. You should tell the research staff 
about all the medications, vitamins and supplements you take and any medical conditions you 
have. This may help avoid side effects, interactions and other risks.
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00034977
Meeting Date Approved 9/26/2018          
Version Valid Until: 1/1/2019


Page 7 of 12
Version 9.4.18
Taking part in this research study may involve providing information that you consider 
confidential or private.  Efforts, such as coding research records, keeping research records secure 
and allowing only authorized people to have access to research records, will be made to keep 
your information safe.
A Data Safety and Monitoring Committee, an independent group of experts, will be reviewing 
the data from this research throughout the study.
In addition, there is a slight risk of a breach of confidentiality.  We will do our best to protect 
your confidential information.  There also may be other side effects that we cannot predict. You 
should tell the research staff about all the medications, vitamins and supplements you take and 
any medical conditions you have. This may help avoid side effects, interactions and other risks.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
If you agree to take part in this study, there may or may not be direct benefit to you. We hope the 
information learned from this study will benefit other people in the future. 
WHAT OTHER CHOICES ARE THERE?
This is not a treatment study. Your alternative is to not participate in this study. There are no 
standard of care alternate treatments or procedures. 
What About My Health Information?
In this research study, any information we collect from you about your health or behaviors is 
considered Protected Health Information. The information we will collect for this research study 
includes: health history, how you respond to study activities or procedures, laboratory and other 
test results, and information from study visits, phone calls, surveys, and physical examinations.
If this research study involves the diagnosis or treatment of a medical condition, then Protected 
Health Information collected from you during this study may be placed in your medical record, 
and may be used to help treat you, arrange payment for your care, or assist with Medical Center 
operations. 
We will make every effort to keep your Protected Health Information private. We will store 
records of your Protected Health Information in a cabinet in a locked office or on a password 
protected computer. 
Your personal health information and information that identifies you (“your health information”) 
may be given to others during and after the study. This is for reasons such as to carry out the 
study, to determine the results of the study, to make sure the study is being done correctly, to 
provide required reports and to get approval for new products.  
Some of the people, agencies and businesses that may receive and use your health information 
are the research sponsor; representatives of the sponsor assisting with the research; investigators 
at other sites who are assisting with the research; central laboratories, reading centers or analysis 
centers; the Institutional Review Board; representatives of Wake Forest University Health 
Sciences and North Carolina Baptist Hospital; representatives from government agencies such as 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00034977
Meeting Date Approved 9/26/2018          
Version Valid Until: 1/1/2019


Page 8 of 12
Version 9.4.18
the Food and Drug Administration (FDA), the Department of Health and Human Services 
(DHHS) and similar agencies in other countries.
Some of these people, agencies and businesses may further disclose your health information. If 
disclosed by them, your health information may no longer be covered by federal or state privacy 
regulations.  Your health information may be disclosed if required by law. Your health 
information may be used to create information that does not directly identify you. This 
information may be used by other researchers. You will not be directly identified in any 
publication or presentation that may result from this study unless there are photographs or 
recorded media which are identifiable.
Monitors, auditors, IRB or other regulatory agencies will be granted direct access to the 
participant’s original medical record for verification of clinical trial procedures or data, without 
violating confidentiality of the participant and to the extent permitted by other applicable laws.
If required by law or court order, we might also have to share your Protected Health Information 
with a judge, law enforcement officer, government agencies, or others. If your Protected Health 
Information is shared with any of these groups it may no longer be protected by federal or state 
privacy rules.
Any Protected Health Information collected from you in this study that is maintained in the 
research records will be kept for at least six years after the study is finished. At that time any 
research information not already in your medical record will either be destroyed or it will be de-
identified. You will not be able to obtain a copy of your Protected Health Information in the 
research records until all activities in the study are completed and finished.
You can tell Dr. Jingzhong Ding that you want to take away your permission to use and share 
your Protected Health Information at any time by sending a letter to this address:
Dr. Jingzhong Ding
However, if you take away permission to use your Protected Health Information you will not be 
able to be in the study any longer. We will stop collecting any more information about you, but 
any information we have already collected can still be used for the purposes of the research 
study. By signing this form you give us permission to use your Protected Health Information for 
this study.
If you choose to participate in this study, your medical record at Wake Forest University Baptist 
Medical Center will indicate that you are enrolled in a clinical trial.  Information about the 
research and any medications or devices you are being given as a participant may also be 
included in your medical record.  This part of the medical record will only be available to people 
who have authorized access to your medical record.  If you are not a patient at this Medical 
Center, a medical record will be created for you anyway to ensure that this important information 
is available to doctors in case of an emergency.
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00034977
Meeting Date Approved 9/26/2018          
Version Valid Until: 1/1/2019


Page 9 of 12
Version 9.4.18
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This website will not include information that can identify you.  At most, the 
website will include a summary of the results.  You can search this Web site at any time.
Laboratory test results and other medical reports created as a result of your participation in the 
research study may be entered into the computer systems of Wake Forest University Health 
Sciences and North Carolina Baptist Hospital.  These will be kept secure, with access to this 
information limited to individuals with proper authority, but who may not be directly involved 
with this research study.
A North Carolina Baptist Hospital (NCBH) medical record will be created for all study 
participants. Information about your participation in the study will be placed in the NCBH 
medical record, along with any routine medical test results that were obtained at NCBH as part 
of this study. 
WHAT ARE THE COSTS?
There are no costs to you for taking part in this study. All study costs, including any study 
medications and procedures related directly to the study, will be paid for by the study. Costs for 
your regular medical care, which are not related to this study, will be your own responsibility.
You will be given a parking voucher so that you do not have to pay for parking when you come 
for your study visits. 
WILL YOUR RESEARCH RECORDS BE CONFIDENTIAL?
The results of this research study may be presented at scientific or medical meetings or published 
in scientific journals.  Your identity and/or your personal health information will not be disclosed 
except as authorized by you or as required by law.  However, there is always some risk that even 
de-identified information might be re-identified. 
Participant information may be provided to Federal and other regulatory agencies as required.  
The Food and Drug Administration (FDA), for example, may inspect research records and learn 
your identity if this study falls within its jurisdiction.
This research is covered by a Certificate of Confidentiality from the National Institutes of 
Health. The researchers with this Certificate may not disclose or use information, documents, or 
biospecimens that may identify you in any federal, state, or local civil, criminal, administrative, 
legislative, or other action, suit, or proceeding, or be used as evidence, for example, if there is a 
court subpoena, unless you have consented for this use. Information, documents, or 
biospecimens protected by this Certificate cannot be disclosed to anyone else who is not 
connected with the research except, if there is a federal, state, or local law that requires 
disclosure (such as to report child abuse or communicable diseases but not for federal, state, or 
local civil, criminal, administrative, legislative, or other proceedings, see below); if you have 
consented to the disclosure, including for your medical treatment; or if it is used for other 
scientific research, as allowed by federal regulations protecting research subjects.
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00034977
Meeting Date Approved 9/26/2018          
Version Valid Until: 1/1/2019


Page 10 of 12
Version 9.4.18
The Certificate cannot be used to refuse a request for information from personnel of the United 
States federal or state government agency sponsoring the project that is needed for auditing or 
program evaluation by the National Institutes of Health which is funding this project or for 
information that must be disclosed in order to meet the requirements of the federal Food and 
Drug Administration (FDA).  You should understand that a Certificate of Confidentiality does 
not prevent you from voluntarily releasing information about yourself or your involvement in 
this research. If you want your research information released to an insurer, medical care 
provider, or any other person not connected with the research, you must provide consent to allow 
the researchers to release it.
WILL YOU BE PAID FOR PARTICIPATING?
You will be paid $60 in gift cards if you complete all the scheduled study visits. If you withdraw 
for any reason from the study before completion you will be paid with a $20 in gift card for each 
complete study visit (baseline, mid-point and follow up).  You can choose from a Walmart , 
Target, or Shell Gas card at each of your visits. You will not be paid for the screening visit.
To receive payment, you must provide your social security number, name and address so that we 
can comply with IRS (Internal Revenue Service) reporting requirements.  When payments are 
reported to the IRS we do not let them know what the payment is for, only that you have been 
paid.  If you do not wish to provide this information you can still take part in this study but you 
will not be paid.
The findings from this research may result in the future development of products that are of 
commercial value. There are no plans to provide you with financial compensation or for you to 
share in any profits if this should occur.
WHO IS SPONSORING THIS STUDY?
This study is being sponsored by the National Institutes of Health and Wake Forest University 
Health Sciences. The sponsor is providing money or other support to Wake Forest University 
Health Sciences to help conduct this study. The researchers do not, however, hold a direct 
financial interest in the sponsor or the product being studied.
WHAT HAPPENS IF YOU EXPERIENCE AN INJURY OR ILLNESS AS A 
RESULT OF PARTICIPATING IN THIS STUDY?
Should you experience a physical injury or illness as a direct result of your participation in this 
study, Wake Forest University School of Medicine maintains limited research insurance 
coverage for the usual and customary medical fees for reasonable and necessary treatment of 
such injuries or illnesses. To the extent research insurance coverage is available under this policy 
the reasonable costs of these necessary medical services will be paid, up to a maximum of 
$25,000. Wake Forest University Baptist Medical Center holds the insurance policy for this 
coverage. It provides a maximum of $25,000 coverage for each claim and is limited to a total of 
$250,000 for all claims in any one year. The Wake Forest University School of Medicine, and 
the North Carolina Baptist Hospitals, Incorporated do not assume responsibility to pay for these 
medical services or to provide any other compensation for such injury or illness. Additional 
information may be obtained from the Medical Center’s Director of Risk and Insurance 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00034977
Meeting Date Approved 9/26/2018          
Version Valid Until: 1/1/2019


Page 11 of 12
Version 9.4.18
Management, at (336) 716-3467.
If you are injured, the insurer may require information such as your name, social security 
number, and date of birth in order to pay for your care.  This is because the insurer is required by 
law to report any payments made to cover the care of any persons who are members of a 
government insurance plan to the Department of Health and Human Services.
You do not give up any legal rights as a research participant by signing this consent form. For 
more information on medical treatment for research related injuries or to report a study related 
illness, adverse event, or injury you should call Dr. Jingzhong Ding at 
 or 
 after hours and identify yourself as a GO MET study participant.
WHAT ARE MY RIGHTS AS A RESEARCH STUDY PARTICIPANT?
Taking part in this study is voluntary. You may choose not to take part or you may leave the 
study at any time. Refusing to participate or leaving the study will not result in any penalty or 
loss of benefits to which you are entitled. If you decide to stop participating in the study we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
safety consequences. The investigators also have the right to stop your participation in the study 
at any time. This could be because: 

it is in your best medical interest, 

your condition worsened, 

new information becomes available, 

you had an unexpected reaction, 

you failed to follow instructions, 

or because the entire study has been stopped.
You will be given any new information we become aware of that would affect your willingness 
to continue to participate in the study.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or in the event of a research-related injury, contact the study 
investigator, Dr. Jingzhong Ding at 
or 
 after hours and identify 
yourself as a GO MET study participant.
The Institutional Review Board (IRB) is a group of people who review the research to protect 
your rights. If you have a question about your rights as a research participant, or you would like 
to discuss problems or concerns, have questions or want to offer input, or you want to obtain 
additional information, you should contact the Chairman of the IRB at 
 or the 
Research Subject Advocate at 
.
You will be given a copy of this signed consent form. 
SIGNATURES
I agree to take part in this study. I authorize the use and disclosure of my health information as 
described in this consent and authorization form.  If I have not already received a copy of the 
Privacy Notice, I may request one or one will be made available to me.  I have had a chance to 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00034977
Meeting Date Approved 9/26/2018          
Version Valid Until: 1/1/2019


Page 12 of 12
Version 9.4.18
ask questions about being in this study and have those questions answered.   By signing this 
consent and authorization form, I am not releasing or agreeing to release the investigator, the 
sponsor, the institution or its agents from liability for negligence.
Subject Name (Printed):_____________________________
Subject Signature: _________________________________ Date: ________Time:_______ am pm 
Person Obtaining Consent:___________________________
Person Obtaining Consent:___________________________ Date:_________ Time:________ am pm
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00034977
Meeting Date Approved 9/26/2018          
Version Valid Until: 1/1/2019