Clinical trial NCT04530747
Conditions: Sleep Apnea, Obstructive
Keywords: Obstructive Sleep Apnea Metformin
Sponsor: Pennington Biomedical Research Center
Start date: 2021-01-28; Completion date: 2021-11-30
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to see if metformin improves metabolism in patients with obstructive sleep apnea (OSA) using positive airway pressure (PAP) therapy. Metformin is approved by the Food and Drug Administration (FDA) for the treatment and prevention of diabetes. It is not approved for use in patients with OSA.

Detailed description:
Positive airway pressure (PAP) is standard therapy for obstructive sleep apnea (OSA) but has shown mixed results for improvement of insulin sensitivity and does not reduce cardiovascular (CV) events and mortality, even in patients with established CV disease. Hence, eliminating intermittent hypoxia alone with standard PAP therapy may not be sufficient to restore metabolism. Additional adjunct strategies (such as metformin) known to improve metabolism may be required to reduce metabolic burden and CV risk in OSA patients. The aim of this study is to examine the longitudinal changes in metabolism of OSA patients receiving both PAP and metformin treatment.

The MET-OSA study will last about 4 months. After screening the participants to determine eligibility, baseline study measures will be obtained and the participants will be provided with standard PAP for OSA treatment. Participants will also be randomized to receive either placebo or metformin treatment for 3 months. Compliance to study drug will be determined during monthly follow-up visits. Final study visit will include assessment of all baseline study measures.

Arms: arm 1: Subjects randomized to this arm will be orally given 2000 mg metformin daily. Metformin dosage will be slowly increased to improve tolerance.

Subjects will also be provided PAP (positive airway pressure) device for standard management of obstructive sleep apnea. arm 2: Subjects randomized to this arm will receive placebo matching study drug. Subjects will also be provided PAP (positive airway pressure) device for standard management of obstructive sleep apnea.
Interventions: intervention 1: Metformin + PAP intervention 2: Placebo oral capsule + PAP
Intervention descriptions: intervention 1: Subjects randomized to this arm will receive 500 mg capsules containing metformin extended release (XR). Metformin XR dosing will be 500 mg (1 x 500 mg) every evening (qPM) during Week 1, 1000 mg (2 x 500 mg) qPM during Week 2, 1500 mg (3 x 500 mg) qPM during Week 3, and 2000 mg (4 x 500 mg) qPM from Week 4 onwards.

Subjects will also be provided PAP (positive airway pressure) device for standard management of obstructive sleep apnea. intervention 2: Subjects randomized to this arm will receive 500 mg capsules containing placebo. Placebo dosing will be 500 mg (1 x 500 mg) qPM during Week 1, 1000 mg (2 x 500 mg) qPM during Week 2, 1500 mg (3 x 500 mg) qPM during Week 3, and 2000 mg (4 x 500 mg) qPM from Week 4 onwards.

Subjects will also be provided PAP (positive airway pressure) device for standard management of obstructive sleep apnea.

Protocol documents:
Prot_SAP_000.pdf: 
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Metabolic Effects of Metformin Therapy in Obstructive Sleep Apnea 
“MET-OSA”
Funding from the Pennington Biomedical NORC
 
PROTOCOL
Principal Investigator: Prachi Singh, PhD
Medical Investigator: Kishore Gadde, MD
LSUHSC-NO Collaborator: Edward C. Mader, Jr, MD
Lab Personnel: Rob Noland, PhD (Co-Investigator on the Grant)
Initial Version: [7/30/2020] Version (1.0)
Revised: [8/24/2020] Version (2.0)
[10/12/2020] Version (3.0)
[11/2/2020] Version (4.0)
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1.
BACKGROUND AND SIGNIFICANCE
Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder which is associated with insulin 
resistance (IR) and metabolic dysfunction.1 As a consequence, OSA patients have a high risk for development 
of diabetes and cardiovascular disease independent of obesity.2, 3 Positive airway pressure (PAP) therapy, 
utilized as standard of care for OSA, resolves pathological intermittent hypoxia (IH) but has poor compliance 
with modest effects on IR and metabolism.4, 5  The limited efficacy of PAP therapy underscores the need to 
develop therapeutic augmentation strategies with the aim to reduce IR and improve metabolic profile to prevent 
diabetes and CVD in OSA patients. Metformin, with its insulin-sensitizing and pleotropic cellular effects, may 
be a good candidate.6, 7
Physiological links between OSA and metabolic dysfunction include sympathetic activation, altered 
hypothalamic-pituitary-adrenal axis, inflammation and oxidative stress.1 While several of these mechanisms 
may readily resolve by mitigation of IH through PAP therapy, chronic IH exposure may have long-lasting effects 
on cellular physiology. Such cellular alterations resulting from chronic IH exposure may not readily reverse with 
elimination of IH and continue to persist to cause tissue dysfunction. We have shown that chronic IH induces 
senescence11 and our preliminary in-vitro data suggest that metformin may attenuate IH induced senescence.
Enduring cellular senescence presents as a compelling mechanism for continued tissue dysfunction in OSA 
patients using PAP. First, recent studies link increased senescence (measured using biomarkers such as 
p16INK4a and γH2AX) to several age- and metabolism-related conditions such as obesity and diabetes.8 
Second, senescence is self-propagating. During senescence, cells undergo growth arrest along with profound 
pro-inflammatory secretome changes through which the neighboring cells also become senescent.8 Third, 
increased senescence causes tissue dysfunction.9 Senescent cells limit tissue regenerative capacity and the 
secretome changes impair cell and tissue function. Therefore, unless removal of senescent cells is targeted, 
tissue dysfunction would likely continue even after mitigation of IH by PAP therapy. Pharmaceuticals with anti-
senescence effects, such as metformin, would be needed to disrupt the senescence cycle and thereby resolve 
tissue IR and restore metabolic profile in OSA patients.
Of note, there has been a renewed interest in the pleiotropic effects of metformin and initial proof-of-concept 
clinical trials are being undertaken to evaluate its benefits on aging and cancer treatment.7  Moreover, while 
animal and in-vitro studies support the anti-senescence effects of metformin, these have not been investigated 
in humans. 
We also propose using metformin as a first-line preventive treatment along with PAP in OSA patients to 
reduce IR for its well-established insulin-sensitizing properties6 and clinical recommendations for diabetes 
prevention. Importantly, the therapeutic benefits of metformin in OSA patients have not been investigated.
2.
STUDY AIMS
Our overarching hypothesis is that in addition to improving insulin sensitivity (IS) via modulating hepatic 
gluconeogenesis metformin therapy will counteract the elevated cellular senescence in OSA patients using 
PAP, and thereby reduce tissue IR and dysfunction. Specifically, we propose that cellular senescence continues 
to persist and propagate in tissue of OSA patients undergoing PAP treatment. Therefore, anti-senescent 
therapeutics such as metformin would benefit OSA patients by improving tissue function and consequent 
metabolic profile. Notably, the role of increased cellular senescence in obesity- and age-related metabolic 
disorders is being increasingly recognized. 8, 9
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To test our hypothesis, we will conduct a double-blind, placebo-controlled, randomized clinical trial in non-
diabetic OSA patients (Apnea hypopnea index, AHI≥15 events/h, HbA1c<6.4%) (fig 1). All participants will be 
provided PAP therapy and adherence will be monitored via monthly compliance visits. In addition, participants 
will be randomized to receive either metformin (2g/day, n=10) or matching placebo (n=10) for 3 months. Study 
measures will be collected at 0 and 3 months to address the following specific aims:
AIM 1: To determine the effects of metformin + PAP on whole body insulin sensitivity (IS). 
Hypothesis: Addition of metformin to PAP therapy in OSA patients will enhance reduction in IR. Measures 
derived from oral glucose tolerance test including Matsuda index (whole body-IS) and ISI-FAA (AT-IS) will be 
used to longitudinally examine changes in IS to inform about metabolic risk reduction in OSA patients.
AIM 2: To evaluate the longitudinal changes in skeletal muscle (SM) and adipose tissue (AT) IS.
Hypothesis: Metformin therapy will improve insulin actions in SM and AT. The effects on metformin/placebo 
therapy on cellular IS will be determined ex-vivo by examining insulin-mediated phosphorylation of AMPK and 
AKT along with insulin-dependent changes in glucose metabolism. These measures will evaluate tissue 
function.
AIM 3: To examine the effects of metformin + PAP on the prevalence of AT and SM senescence.
Hypothesis: Compared to placebo, metformin will reduce AT and SM senescence burden. Multiple biomarkers 
of senescence including p16INK4A, γH2AX, phospho-p53, and senescence-associated β-galactosidase (SA β-
gal)8 activity will be measured to identify changes in prevalence of senescent cells. The outcome will inform 
about the progression of senescence in PAP treated OSA patients and its mitigation by metformin. 
3.
RESEARCH DESIGN
We will conduct a double-blind, placebo-controlled, randomized proof-of-concept RCT in 20 non-diabetic 
OSA participants (fig 1). After baseline measures are obtained, all participants will be asked to initiate and 
adhere to PAP therapy. Participants will be randomly assigned in a 1:1 ratio to receive placebo or metformin 
for 3 months. 
All study visits will take place at Pennington Biomedical Research Center (PBRC). Qualifying sleep study 
will be conducted at PBRC and the data will be shared with our research collaborators (LSUHSC-NO, Dr. 
Mader) and ApneaMed to determine eligibility and obtain PAP devices. PAP devices will be provided at PBRC 
Fig 1: Schematic of the study design. Study measures will be obtained at baseline and at 3-month follow-up. Monthly compliance visits 
will monitor adherence to PAP and study drug. Participants will also undergo comprehensive phenotyping to assess metabolic risk.
Double blind
N=10
•3 month follow-up
•Repeat  baseline 
measures
RANDOMIZATION
PLACEBO
METFORMIN
PAP
OSA
(AHI>15)
BASELINE MEASURES
•
OGTT
•
Abdominal fat biopsy
•
Skeletal muscle biopsy
N=20
N=10
•3 month follow-up
•Repeat  baseline 
measures
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and treatment will be administered online. Eligible participants will remain in the study for up to 4 months. The 
study will take place over a period of 1 year.
4.
INVESTIGATIONAL DRUG (Metformin/Placebo)
4.1 Clinical Data to Date
Metformin is the most popular oral glucose-lowering drug worldwide. It has an excellent long-term safety 
profile with most professional guidelines recommending it as the first-line oral therapy for type 2 diabetes. 
Although not formally approved for prediabetes, it is commonly used for treatment of this condition. Importantly, 
even though OSA patients are at high risk for development of diabetes, specific recommendations related to 
use of metformin in OSA patients are lacking.
4.2 Risks 
The most common adverse effects of metformin are diarrhea, abdominal discomfort and nausea, which are 
dose-related. Other adverse effects include a metallic taste and mild anorexia. These symptoms are usually 
mild, transient, and reversible after dose reduction or discontinuation of the drug. About 5% of patients cannot 
tolerate the gastrointestinal adverse effects of metformin. Malabsorption of vitamin B12 may lead to its 
deficiency during long-term metformin therapy although a precise estimate of the frequency of this adverse 
effect is not available. Metformin-associated lactic acidosis (MALA), a serious condition, is very rare, with an 
estimated incidence of 3-10 per 100,000 person-years. Risk for MALA is increased when renal clearance is 
decreased and drug levels rise very high. In 2016, FDA issued the following safety communication: 
1.
obtain the patient’s estimated glomerular filtration rate (eGFR) prior to starting metformin. 
2.
metformin is contraindicated in patients with an eGFR below 30 mL/min/1.73 m2. 
3.
starting metformin in patients with an eGFR between 30-45 is not recommended. 
4.
obtain eGFR at least annually. 
5.
assess benefits and risks of metformin if eGFR falls below 45. 
6.
discontinue metformin if eGFR falls below 30.
7.
withhold metformin at the time of iodinated contrast imaging procedure in patients with eGFR 
between 30-60, in the setting of liver disease, alcoholism, or heart failure, or if intra-arterial contrast 
is used, with further recommendation that metformin may be restarted after 48 hours if renal function 
remains stable.
Participant selection criteria for our study are designed to minimize risks of metformin. To reduce the risk 
of gastrointestinal adverse effects, we will exclude participants with prior intolerance to metformin. This protocol 
allows for withholding or delaying dose escalation and dose reduction. At screening, to minimize the risk of 
MALA, we will assess eGFR and exclude participants with eGFR <60 mL/min/1.73m2 (CKD-EPI method). Our 
eGFR exclusion criterion is more conservative than the FDA recommendation of not starting metformin in 
patients with eGFR <45. As noted above, the potential for lowering of B12 levels is only a concern during long-
term metformin therapy. In the context of 3-month metformin treatment, monitoring for B12 levels is not 
warranted. The study will exclude participants who are pregnant or breastfeeding and those planning to become 
pregnant. Women of childbearing potential will be required to have a negative pregnancy test prior to starting 
the study drug.
4.3 Dose Rationale
Dosing of metformin XR in this study is in line with the drug’s FDA-approved prescribing information.
4.4 Treatment Regimen
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This RCT will compare metformin XR vs placebo. Each visually indistinguishable study drug capsule will 
contain metformin XR 500 mg or placebo. Metformin XR dosing will be 500 mg (1 x 500 mg) qPM during Week 
1, 1000 mg (2 x 500 mg) qPM during Week 2, 1500 mg (3 x 500 mg) qPM during Week 3, and 2000 mg (4 x 
500 mg) qPM from Week 4 onwards. Placebo dosing will be identical. For participants tolerating the study drug 
well, dosing will remain at 4 capsules qPM. Based on tolerability, scheduled dose increases may be delayed, 
or dose reduced to a tolerable level. Also, based on tolerability or subject preference, dosing schedule may be 
changed to BID (twice daily) rather than taking all 4 capsules qPM. Use of 4 capsules allows for this flexibility 
to match clinical practice. Participants who are unable to tolerate even one capsule (metformin 500 mg or 
placebo) may stop the study drug and continue to provide study assessments. Participants will be given detailed 
instructions at the time of dispensing and instructed to return unused medication. The capsules dispensed and 
returned will be recorded on a log-sheet. Expired or returned study drug will be destroyed on-site per PBRC 
policy by the Research Pharmacy. Destructions are also documented in log-sheets.
4.5 Study drug preparation and masking
The study will be conducted in a double-blind manner. The study statistician and research pharmacist will 
be the only personnel who will have information about randomization and treatment assignment. PBRC 
research pharmacist will procure metformin, repackage the active drugs and placebo in identically appearing 
capsules, and dispense at monthly visits. Investigators and all other study personnel and the study participants 
will be blinded to the treatment assignment until participants have completed all visits and all data have been 
entered and the data file has been locked to prevent changes.
4.6 Prior and Concomitant Therapy
Individuals taking certain prescription medications including antihistamines (cetirizine, fexofenadine, 
desloratadine, loratadine, etc.), oral contraceptive pills, antacids, proton pump inhibitors, antidepressants, 
diuretics, or intrauterine devices will be included in the study and allowed to continue with the treatment. 
Participants will be instructed to not make changes to their medications including over-the-counter medicines, 
vitamins, and supplements. Any changes in medications will be monitored. The PI and MI will decide if the 
changes in medication will allow continuation in the study. Participants will be encouraged to initiate and strictly 
adhere to standard PAP therapy for OSA treatment. PAP therapy would be initiated via collaborating DME. 
Participants who are unable to tolerate CPAP may discontinue CPAP and continue in the study to provide study 
assessments. They will be advised to consult with their primary care physician regarding alternative treatments 
for OSA after completing the study. Since OSA is a chronic condition that does not pose an imminent threat to 
a person’s health, given the short duration of the study, we believe that a short delay in receiving alternative 
therapy is reasonable.
5.
STUDY POPULATION
5.1 Subject Population
We will enroll up to 20 untreated OSA patients. The study may need to screen up to 60 participants to enroll 
20 participants in the RCT.
5.2 Inclusion Criteria
Eligibility criteria include: 

Age 35-65 years (inclusive).

Body mass index (BMI) ≥ 30-50 kg/m2 (inclusive).
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
Apnea-Hypopnea Index ≥ 15 events/h.

Must be able to provide written informed consent. 

Willing to participate and adhere to study procedures (video recorded in-lab sleep studies, PAP 
treatment, take study drug, have adipose tissue and skeletal muscle biopsies).

Women of child-bearing potential must agree to use appropriate contraception to avoid 
pregnancy throughout the study.

Willing to have blood, as well as adipose and muscle tissue stored for future use.
5.3 Exclusion Criteria
Study volunteers are ineligible to participate (or will be excluded from participating in this study) if they meet 
any of the following criteria:

HbA1c > 6.4%.

Severe or uncontrolled hypertension defined as systolic BP ≥180 mmHg and/or diastolic BP 
≥110 mmHg on the average of three seated measurements after being at rest for at least 5 
minutes.

Significant cardiovascular, hepatic, renal, neurologic, or psychiatric disease as determined by 
the study physician.

Pregnancy, breast feeding or planning pregnancy in the coming 4 months.

Impaired renal function defined as eGFR <60ml/min/1.73m2 (estimated with CKD-EPI method).

Known hypersensitivity to metformin.

Currently taking a glucose lowering or weight loss medications.

Current PAP use or use of PAP in the past 6 months.

Currently taking antihypertensive and lipid-lowering medications known to affect adipose tissue 
and skeletal muscle metabolism. For example, statins and drugs targeting renin-angiotensin 
system will not be allowed. However, use of diuretics, beta-blockers, alpha-blockers and 
calcium channel blockers may be allowed provided the participant is on a stable dose for at 
least 3 months prior to the study visit. 

Oxygen desaturation index <15 events/h of sleep. 

Any medication or condition that, in the opinion of the medical investigator, could interfere with 
the study outcomes or put the subject at risk by participating in the study.
6.
RECRUITMENT
Community advertisements, including targeted and passive outreach (e.g., web, Listserv, community 
events, etc.), and promotional materials will be used. Eligible OSA patients and patients with high risk for OSA 
may also be referred through local Clinics (Sleep Foundation, Baton Rouge General, Our Lady of the Lake 
etc.). Study staff will explain the study and procedures to interested individuals and may provide them with a 
copy of the consent form for further explanation. Following determination of initial eligibility (e.g., BMI, age, 
willingness to undertake study procedures), a fasting screening visit will be scheduled.
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7.
ASSESSMENT SCHEDULE AND PROCEDURES
An overview of all clinic visits and assessments is presented in Table 1. Eligibility of the study participants 
will be determined during two screening visits. Study procedures will require 4 visits. Among the study visits, 
Visit 3 and Visit 6 will last ~ 4.5 h each during which baseline and 3-month follow-up measures will be obtained. 
Visit 4 and Visit 5 will comprise of short (~ 45 min) visits during which compliance to study drug and PAP would 
be monitored and study drug will be dispensed.
Table 1: Clinic Visits and Assessments
Test Period
Assessment
Screening 
Visit 1
Screening 
Visit 2
Visit 3
Baseline 
Visit 4
Month 1 
Visit 5
 Month 2 
Visit 6
Month 3 
Informed consent
X
Inclusion/exclusion criteria 
X
Medical History (Health 
Questionnaire)
X
Physical examination
X
Concomitant medications
X
Vital Signs (BP, pulse)
X
Body weight
X
X
X
Height and BMI
X
Oximetry 
X
Blood draw (fasting)
X
X
X
Overnight Sleep study
X
Waist, hip, neck, 
circumference
X
X
OGTT
X
X
Urine Pregnancy testing* 
X
X
Questionnaires
X
X
Dietary assessment (food 
record)
X
X
Whole body DXA
X
X
Abdominal fat biopsy
X
X
Muscle biopsy
X
X
ABPM -24 hour
X
X
PAP provided
X
Randomization
X
Drug Dispense
X
X
X
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*urine pregnancy testing is only for women of childbearing potential. BP: blood pressure; BMI: body mass index, 
OGTT: oral glucose tolerance test; DXA: dual energy X-ray absorptiometry; ABPM: ambulatory blood pressure 
monitoring; PAP: positive airway pressure.
8.
SCREENING 
8.1
Screening Visit 1
Study volunteers will arrive at PBRC for an early morning fasting visit. During this visit, participants will 
provide informed consent prior to the initiation of any study procedures. The informed consent process will be 
conducted primarily by the study coordinator, but also on occasion by the study PI (Dr. Prachi Singh) or by a 
trained clinic staff. Potential enrollees will be given ample time to read the informed consent and ask questions 
about the study. After signing the consent form, physical examination will be conducted to ensure inclusion 
criterion is being met. Height, weight, and vital signs (blood pressure, heart rate) will be measured. Medical 
history will be reviewed via screening health questionnaire and concomitant medication determined for 
exclusionary criteria. In addition, participants will have blood drawn for measurement of chem15 panel (includes 
creatinine to determine eGFR via CKD-EPI method, and other electrolytes and hepatic enzymes), and HbA1c. 
If all immediately available eligibility criteria are satisfied, eligible volunteers will be provided oximeters to 
measure changes in blood oxygen saturation during sleep at home. 
8.2
Screening Visit 2
Participants with oxygen desaturation index (ODI) >15 events/h of sleep will proceed to screening visit 2. 
During this visit an overnight sleep study (including video recording) will be conducted in PI’s lab.  The sleep 
study data will be read and interpreted by Sleep Board Certified Physician (Dr. Mader – LSUHSC-NO) and/or 
ApneaMed. Required PAP prescription will be provided to ApneaMed for procurement of PAP devices. 
9.
METHOD FOR ASSIGNING PARTICIPANTS TO TREATMENT GROUPS (RANDOMIZATION) 
After confirmation of eligibility criteria, participants will be randomized to receive either placebo or metformin 
in a 1:1 ratio. Robbie Beyl, PhD, the study statistician, will perform the randomization, and the study drug 
assignment will be implemented by Claire Hazlett, investigational pharmacist. Randomization will be done using 
a dynamic allocation based on age and OSA severity determined by Apnea Hypopnea Index (AHI).
10. STUDY VISITS
10.1 Visit 3 (Baseline)
Participants will arrive to PBRC for an early morning fasting visit. Body weight will be measured along with 
measurement of waist, hip, arm and neck circumference. Blood sample will be drawn, questionnaires will be 
administered, and if needed, urine pregnancy test will be conducted. Participants will be given a standard 
glucose drink (75g glucose) to consume while timed blood samples will be collected every 30 min for 2 hours 
to measure glucose, insulin and free fatty acids (FFA). An abdominal adipose tissue biopsy and a skeletal 
muscle biopsy will be performed. Participants will also undergo whole-body DXA to determine body 
composition. At the end of this visit, participants will be provided a monitor to measure 24-h ambulatory blood 
Adverse events 
X
X
X
Monitoring adherence
(PAP and Drug)
X
X
X
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pressure and study drug will be dispensed with appropriate dose and safety instructions. Lunch will be provided 
prior to discharging the participants.
Following this visit, we will provide the study participants with PAP therapy through standard on-line 
resources (ApneaMD). PAP devices will be given to the participants at PBRC. PI will obtain equipment serial 
number to monitor adherence. For the first 4-weeks, study personal will monitor PAP compliance weekly (on-
line data). Thereafter, we will monitor compliance on a monthly basis. Appropriate PAP use will be encouraged 
via additional consults and/or mask replacement as needed.
10.2 Visit 4 (Month 1) and Visit 5 (Month 2)
During this visit, participants will be asked to bring remaining study drug to determine compliance. 
Participants will also be questioned for any possible side-effects and adverse events.
Non-compliant participants (<80% drug taken as determined by pill count10) will be interviewed to determine 
factors that resulted in poor compliance. If needed, guidance will be provided to improve management of minor 
side-effects which may improve adherence such as bloating etc. Patients will continue in the study but will be 
counselled on the importance of taking their medication as prescribed by the study protocol.
Compliance to PAP therapy for OSA will also be monitored through cloud-based technology. Non-compliant 
participants (using PAP <4hours each night) will be interviewed to determine factors resulting in poor 
adherence. If needed, participants may be referred to consulting DME (ApneaMed) /physician (Dr. Mader) to 
help improve CPAP adherence.  
All participants will be reminded to continue /improve adherence for both PAP and study drug. 
Study drug for the next ~30 days will be dispensed. 
10.3 Visit 6 (Month 3/ End-of-Study)
All procedures from Visit 3 will be repeated and any remaining study drug will be collected and disposed. 
Additionally, information related to potential adverse events will also be collected. 
11. MEASUREMENTS AND OUTCOME ASSESSMENTS
11.1 Questionnaires
Participants will complete a Screening Health Questionnaire at Screening Visit 1 only. Participants will be 
asked to complete other questionnaires including the Epworth Sleepiness Scale, Pittsburgh Sleep Quality 
Index, and International Physical Activity Questionnaire during Visit 3 and Visit 6.
Screening Health Questionnaire: The Screening Health Questionnaire is a 25-item questionnaire 
that assesses general health and medical history (e.g., medical conditions, diet and exercise habits, 
reproductive health).
Epworth Sleepiness Scale (ESS): The ESS is an 8-item questionnaire intended to measure daytime 
sleepiness. The questionnaire asks individuals to rate the probability of falling asleep on a scale of 
increasing probability (from 0 to 3) for 8 different situations during their daily lives, though not 
necessarily every day. The scores for the eight questions are added together to obtain a single total 
score. A total score of 11-15 indicates excessive daytime sleepiness, while a score of ≥16 indicates 
the possibility of severe sleep apnea or narcolepsy.5
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Pittsburgh Sleep Quality Index (PSQI): The PSQI is used to assess sleep quality over a 1-month 
time period. The measure consists of 19 individual items, creating 7 components that produce one 
global PSQI score. The 7 component scores consist of: 1) subjective sleep quality; 2) sleep latency 
(i.e., how long it takes to fall asleep); 3) sleep duration; 4) habitual sleep efficiency (i.e., the percentage 
of time in bed that one is asleep); 5) sleep disturbances; 6) use of sleeping medication; and 7) daytime 
dysfunction. Each item is weighted on a 0-3 interval scale. The global PSQI score is then calculated 
by totaling the 7 component scores, providing an overall score ranging from 0-21, where lower scores 
denote a healthier sleep quality.6 
International Physical Activity Questionnaire IPAQ: The IPAQ is a well validated instrument used 
to estimate physical activity across a comprehensive set of domains including leisure time physical 
activity, domestic and gardening activities, work-related physical activity and transport-related physical 
activity.
11.2 Fasting Blood Draw
A fasting blood sample will be taken at Screening Visit 1 to assess inclusion criteria and overall health 
(HbA1c, Chem15 including ALT, creatinine, lipid panel and glucose), as well as during Visit 3 and Visit 6 to 
measure insulin, glucose, and free fatty acids (FFA). HbA1c and measures of Chem15 panel will also be 
obtained at Visit 6. Fasting blood will also be archived at Visit 3 and Visit 6. 
11.3 Overnight oximetry
Pulse oximeters (Nonin WristOX2) will be provided to the participants during Screening Visit 1 to determine 
risk for sleep apnea. Participants will be asked to use the oximeter for one night of sleep. Determination of 
nocturnal oxygen desaturations to objectively asses risk for sleep apnea will be important to reduce screen 
failures. Only participants with oxygen desaturation index (ODI) >15 events/h of sleep will be asked to 
participate in the overnight sleep study. Participants may be asked to repeat oximetry if incomplete data are 
obtained.
11.4 Overnight sleep study (Polysomnography, PSG)
Overnight video PSG will be performed in individuals with ODI >15 events/h at PI’s lab at Screening Visit 
2. PSG will include electroencephalography, electrooculography, electromyography, electrocardiography, 
pulse oximetry, nasal pressure transducer, oronasal thermocouple, calibrated respiratory inductance 
plethysmography. Sleep staging and events will be scored by registered PSG technologists according to AASM 
established criteria and report will be finalized by a Sleep Board Certified Physician (Dr. Mader).11 PAP 
prescription will be generated for the eligible participants and provided to ApneaMed to procure appropriate 
PAP device.
11.5 Body Composition (by Dual-Energy X-ray Absorptiometry)
Dual-energy X-ray absorptiometry (DXA) scans will be performed at the Imaging Facility of PBRC at Visit 3 
and Visit 6. Total adiposity and regional fat mass will be assessed with DXA using a whole-body scanner (Lunar 
iDXA; General Electric, Milwaukee, WI). The DXA protocol requires that participant lie on a table wearing a 
hospital gown and with no metal objects on them while both legs will be placed together using two Velcro straps. 
The scanner emitting low energy X-rays and a detector passes along the body. The scan takes ~10 minutes 
and the radiation dose is less than 1 mrem, equal to about 12-h of background radiation. The scans will be 
analyzed with the latest software. The software version is enCORE 13.6. We will run quality control scans on a 
daily basis, and GE has indicated that accuracy of the data is confirmed with these daily QC scans. If needed, 
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a pregnancy test will be given before DXA scans to confirm absence of pregnancy. Fat mass will be calculated 
by taking the metabolic weight (i.e., total body weight minus gown weight) multiplied by the regional percent 
body fat given by the DXA.
11.6 Three-day Dietary Records  
Participants will be given instruction and a form to complete dietary record for 3 non-consecutive days which 
would include 2 weekdays and 1 weekend during Visit 3 and Visit 6. This would provide rough estimation of the 
participants’ normal daily intake and any changes that may be mediated by PAP and/or metformin treatment. 
11.7 Oral Glucose Tolerance Test
Glucose tolerance will be assessed using an oral 75 g oral glucose tolerance test (OGTT). Participants will 
be studied after an overnight fast. An intravenous line will be placed and one baseline sample will be drawn at 
-5 minutes. The participants will then consume a 75 g glucose beverage within 5 minutes. Blood samples will 
be collected at 30, 60, 90, and 120 to measure serum glucose, insulin and free fatty acid concentrations. Whole 
body insulin sensitivity will be calculated using Matsuda index (10,000/ √[fasting glucose X fasting insulin] X 
[mean OGTT glucose X mean OGTT insulin]) and other indices related to whole body glucose homeostasis. 
Adipose tissue insulin sensitivity will be calculated using ISI- FFA [2/(Insulin AUC X FFA AUC) +1].12  
11.8 Ambulatory Blood Pressure Monitoring
Ambulatory 24-hour blood pressure (BP) and heart rate will be continuously collected via an Ambulatory 
BP Monitor (or ABPM) starting in the afternoons of Visit 3 and Visit 6. The system will be programmed to record 
blood pressure and heart rate every 30 minutes during the day and night. The blood pressure cuff will be placed 
on the non-dominant arm. Both written and oral instructions pertinent to the use of ABPM will be provided to all 
participants. Volunteers will be instructed to avoid caffeine, alcohol, moderate-to-vigorous exercise, and 
daytime naps during this period and asked to maintain an Activity Log (bedtimes, mealtime, physical activity, 
showering, etc.). Participants taking antihypertensive medications will be instructed to adhere to their prescribed 
dosing. The ABPM records key aspects of blood pressure including 24-hour, daytime and nighttime systolic 
BP, diastolic BP, mean BP, and heart rate. Participants may be asked to repeat the blood pressure monitoring 
if incomplete data are obtained.
11.9 Biopsies
On the mornings of Visit 3 and Visit 6, skeletal muscle and adipose tissue biopsies will be performed in the 
PBRC Inpatient Unit on the non-dominant side of the body.
11.9.1 Skeletal Muscle Biopsy
A vastus lateralis muscle biopsy will be performed using a Bergstrom needle in the PBRC Inpatient Unit. 
After cleansing the skin on the non-dominant side of the leg with povidone-iodine solution and placement 
of a sterile drape, topical anesthesia will be administered using a 50%/50% mixture of bupivacaine 0.5% 
and lidocaine 2%. The skin will be incised (0.75 cm) with a #11 scalpel. The fascia fibers are separated with 
the blunt edge of the scalpel and the Bergstrom needle inserted into the vastus lateralis. After suction is 
applied, tissue will be cut and removed. Several passes will be used to obtain up to 500 mg of muscle 
tissue. Pressure will then be applied and the skin closed with sterile tape. After cleaning the sample, tissue 
will be processed immediately to develop primary myotubes, while the remaining tissue will be snap frozen 
in liquid nitrogen and stored for subsequent analyses.
11.9.2 Adipose Tissue Biopsy
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A subcutaneous abdominal adipose tissue (two-thirds from the umbilicus to the anterior superior iliac 
spine) will be performed in the PBRC Inpatient Unit. After cleansing the skin on the non-dominant side of 
the abdomen with povidone-iodine solution and placement of a sterile drape, topical anesthesia will be 
administered using a 50%/50% mixture of bupivacaine 0.5% and lidocaine 2%. The skin will be incised 
(0.75 cm) with a #11 scalpel. The fascia fibers are separated with the blunt edge of the scalpel and a 
Bergstrom needle and Mercedes lipoaspirate technique will be applied. After aspiration is applied, ~1.5-2 
grams of adipose tissue will be extracted. Pressure will be applied and the skin closed with sterile tape.
11.9.3 Tissue biopsy analysis
Tissue samples obtained from the biopsy will be used to address the hypothesis stated in Aim 2 and Aim 
3. As shown in Table 2, skeletal muscle and adipose tissue samples will be used specifically for: 1) ex-vivo 
determination of insulin signaling; 2) determination of insulin-stimulated GLUT4 translocation determined 
by confocal imaging; 3) determination of the prevalence of senescence biomarkers (p16INK4A, γH2AX, 
phospho-p53, and SA β-gal) and SASP using confocal imaging, Western blot, and mRNA quantification; 4) 
establishment of primary cultures to measure basal and insulin stimulated glycogen synthesis and 
lipogenesis using [U-14C]glucose13, 14; 5) measurement of basal and insulin stimulated glucose uptake using 
[3H]-2-deoxyglucose; and 5) a tissue archive for future analyses. These ex-vivo studies will be performed 
in Dr. Singh’s and Dr. Noland’s lab.
Table 2: Planned tissue analysis.
Aim 2
Aim 3
Tissue 
Type
Total 
Primary 
Culture
Insulin 
signaling
GLUT4 
location
Confocal
RNA
Western 
blots
Secretome
β-gal 
staining
SM 
(mg)
500
150
50
80
25
25
50
-
-
AT 
(mg)
1500
300
100
200
50
50
100
75
75
SM: Skeletal muscle, AT: adipose tissue.
11.10 Compliance procedures

Medication reconciliation: Adherence to study drug regimen will be determined by examining the 
medication possession ratio and the proportion of days covered on a monthly basis. Participants taking 
study drug ≥80% will be considered compliant.

PAP adherence: Study participants will be provided with standard PAP therapy. PAP usage will be 
monitored using real-time data acquisition by cloud-based software on a weekly basis during the initial 
weeks and later on a monthly basis. If low compliance is observed, participant will be contacted to 
improve adherence and referred for further PAP adjustment, if needed.
12 COMPENSATION
Participants will receive up to $300 for completion the study ($100 for Visit 3, $25 each for Visit 4 and Visit 
5, and $150 for Visit 6/ End-of-Study). 
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Participants will not be compensated for screening visits. Payment will be received via check requested 
from the LSU payroll department. 
All eligible participants will be provided PAP equipment for the study duration and allowed to keep the 
equipment for continued OSA treatment after the study is completed. Participants would be advised to follow-
up with a Sleep-board certified physician for clinical care.
13 PATIENT SAFETY AND CONFIDENTIALITY
13.3 Consent
Consent will be obtained upon screening before initiating study specific procedures. A quiet, comfortable, 
and private setting for the informed consent process will be provided. The consent process will be explained to 
the subject, time will be provided to consider all options and when possible, the subject will be provided a copy 
of the consent form well in advance for review at home. Study staff will consider the subject’s likely reading 
abilities and provide an impartial witness in the informed consent process if necessary. All questions will be 
answered. Coercion or other undue influences will be avoided through the use of a quiet, comfortable, and 
private setting will be used for the informed consent process. The subject will be told that informed consent can 
be revisited at any time and consent can be withdrawn at any time without affecting the subject’s medical care. 
The informed consent process will continue throughout the subject’s participation in the study and consent will 
be informally verified on a continuing basis. Significant new information will be given to the subject as it is 
available.
13.4 Risks to Participants
This Human Subjects Research meets the definition of a Clinical Trial. This study does not involve major 
risk to participants. Efforts to minimize the potential risks of the assessment methods and outcome variables 
include frequent monitoring by the investigators to assure that no volunteer suffers any adverse effects from 
participating in the research. 
The known risks, inconveniences, or side effects from the proposed procedures in the project are included 
here (in alphabetical order):
Potential Risks and Efforts to Minimize the Risks
Procedure
Potential Risks
Efforts to Minimize the Risks
Adipose 
Tissue 
Biopsies
Pain, infection, scaring, bleeding, and loss of 
sensation to the skin (usually temporary but 
in some cases permanent) around biopsy 
sites are possible risks.  
Trained nurses and personnel will be 
performing the biopsies using sterile 
technique after local anesthesia to 
minimize risks.
Ambulatory Blood 
Pressure 
Monitoring
There are no known risks associated with 
the 
blood 
pressure 
monitor. 
Some 
discomfort having the cuff inflate every 30 
minutes 
around 
the 
clock 
may 
be 
experienced.
The device can easily be removed 
should 
the 
subject 
become 
uncomfortable.
Blood Draws
Bruising, bleeding, pain, and infection pose 
minimal risks. 
Trained phlebotomists and personnel 
will use sterile technique.
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Confidentiality 
of 
Data
Taking part in this research may involve 
providing information that one considers 
confidential or private. There is a slight risk 
that data could be revealed inappropriately 
or accidentally 
Study researchers and staff will take 
steps to protect data that is collected. 
Efforts, such as coding research 
records, keeping research records 
secure and allowing only authorized 
people to access research records, will 
be made to keep the data safe.
Dual-Energy 
X-
Ray 
Absorptiometry 
(DXA)
DXA measures the amount of bone, muscle, 
and fat in the body. The expected dose of 
radiation is minimal, equivalent to less than 
0.0004mSv or ~12 h of exposure to the sun.
The amount of radiation used for this 
procedure is very small. The radiation 
dose for a DXA scan is equivalent to the 
radiation an individual is naturally 
exposed to in the environment in less 
than one day. Scans will not be 
performed on any subject who is 
pregnant. A pregnancy test will be 
performed within 72 hours before the 
scan on females of child-bearing-
potential.    
Lifetime radiation exposure: We are 
exposed to radiation in the environment 
on a daily basis; however, some 
scientists have suggested that humans 
have a lifetime maximum exposure 
limit. Exposure to radiation is not 
without risk, but it is difficult to quantify 
the exact amount someone is exposed 
to. By participating in this study, 
individuals will be exposed to radiation 
that will add to this lifetime maximum 
exposure limit. If participants believe 
that they have been exposed to a 
significant amount of radiation as part of 
your occupation or due to treatment for 
a specific medical condition, they would 
be asked to notify the study team to 
discuss whether this study would be 
appropriate for them.
Fasting for 10-h
Nausea. 
Light snacks will be available to eat 
once fasting procedures completed.
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Oral 
Glucose 
Tolerance 
Test 
(OGTT)
There is a possibility of pain, bruising, or 
infection at the site of the needle insertion for 
the IV line. The drink may cause nausea, 
vomiting, abdominal bloating or a headache. 
Trained nurses and personnel minimize 
the risk associated with IV. Participant 
may choose to drink the glucose 
solution more slowly or stop drinking 
completely.
Oximetry
There are no significant risks related to 
overnight use of oximeter other than 
temporary discomfort while wearing the 
device.
The device can easily be removed 
should 
the 
subject 
become 
uncomfortable.
Questionnaires
Uncomfortable answering questions.
Participants may skip any questions.
Skeletal 
Muscle 
Biopsies
Pain, infection, scaring, bleeding, and loss of 
sensation to the skin (usually temporary but 
in some cases permanent) around biopsy 
sites are possible risks.  
Trained nurses and personnel will be 
performing the biopsies using sterile 
technique after local anesthesia to 
minimize risks.
Sleep Study
There are no significant risks related to sleep 
study (polysomnography). However, to 
obtain 
the 
polysomnographic 
measurements, it may be necessary to glue 
many small surface electrodes on the 
participant’s scalp and face. The adhesive 
used to attach these wires has a strong 
smell, and the subject may feel a scratching 
sensation when the wires are applied.
Trained 
personnel 
will 
place 
the 
electrodes using adhesives approved 
for sensitive skin.
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Study 
drug 
(metformin)
Common 
side-effects 
associated 
with 
metformin 
use 
include 
diarrhea, 
gas 
(flatulence), upset stomach (throwing up) 
and feeling tired or weak. Uncommon or rare 
side 
effect 
might 
include 
metformin-
associated lactic acidosis. This extremely 
rare side effect may be severe enough to 
cause death, hypothermia, hypotension, and 
resistant bradyarrhythmias. 
The GI associated side-effects will be 
minimized by using the extended 
release formulation and following an 
individualized 
dose 
escalation 
schedule. We will also minimize the risk 
of lactic acidosis by asking study 
participants to stop taking the study 
medicine and contacting the study 
investigators within 24 hours if they 
develop symptoms including malaise, 
myalgias, 
respiratory 
distress, 
somnolence 
and 
abdominal 
pain. 
Importantly, individuals with a higher 
risk for metformin-associated lactic 
acidosis include renal impairment, 
concomitant use of certain drugs, old 
age 
(≥80 
years), 
and 
hepatic 
impairment will be excluded from study 
participation. Furthermore, individuals 
in whom metformin should be used with 
caution, including pregnant or nursing 
women are not included in the study.
In addition to the risks listed above, participants may experience a previously unknown risk or side effect.
13.5 Safety Monitoring
13.5.1 Personnel responsible for the safety review and its frequency 
The Principal Investigator (Dr. Prachi Singh, PI) and the Medical Investigator (Dr. Kishore Gadde, MI) 
will be responsible for monitoring the data, assuring protocol compliance and conducting the safety reviews 
on a quarterly basis (including at the time of continuing review). During the review process, the Principal 
Investigator will evaluate whether the study should continue unchanged, requires modification/amendment 
or should close to enrollment. Findings will be reported at the time of continuing review. The IRB, PI or 
regulatory body (e.g., FDA, OHRP) has the authority to stop or suspend the study or require modifications.
13.5.2 Determination of study risk
The risks associated with the current study are deemed moderate for the following reasons: 

We do not view the risks associated with the study procedures including metformin use, fat biopsy 
and muscle biopsy as minimal. 

Given the established safety and validity of metformin and biopsy procedures in our prior work, we 
do not view the proposed study as high-risk. 
Although we have assessed the proposed study as one of moderate risk, the potential exists for 
anticipated and/or unanticipated adverse events, serious or otherwise, to occur since it is not possible to 
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predict with certainty the absolute risk in any given individual or in advance of firsthand experience with the 
proposed study methods. Therefore, we provide a plan for monitoring the data and safety of the proposed 
study as follows: 
13.5.2.1
Adverse events 
In this study, an adverse event or experience is defined as any health-related unfavorable or 
unintended medical occurrence that happens throughout study participation. Examples of adverse 
events include but are not limited to the following: 

A clinically significant laboratory or clinical test result.

An event that results in missing a study visit.

An event that requires a visit to a physician.

An event that occurs as a result of a study procedure.

Unanticipated or untoward medical events that may be study related.
13.5.2.2
Attribution of adverse events
Adverse events for each subject participating in the study will be monitored and attributed to the 
study procedures/design by the Principal Investigator (PI) (Prachi Singh, PhD) and/or Medical 
Investigator (MI) (Kishore Gadde, MD) according to the following categories: 

Definite: Adverse event is clearly related to investigational procedure(s)/agent(s). 

Probable: Adverse event is likely related to investigational procedure(s)/agent(s). 

Possible: Adverse event may be related to investigational procedure(s)/agent(s). 

Unlikely: Adverse event is likely not related to the investigational procedure(s)/agent(s). 

Unrelated: Adverse event is clearly not related to investigational procedure(s)/agent(s). 
13.5.2.3
Plan for grading adverse events
The following scale will be used in grading the severity of adverse events noted during the study: 

Mild adverse event 

Moderate adverse event 

Severe or medically significant
13.5.2.4
Plan for determining seriousness of adverse events
In addition to grading the adverse event, the PI and MI will determine whether the adverse event 
meets the criteria for a Serious Adverse Event (SAE). An adverse event is considered serious if ANY of 
the following apply: 

It is life-threatening.

It results in inpatient hospitalization or prolongation of existing hospitalization.

It results in persistent or significant disability or incapacity. 
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
It results in a congenital anomaly or birth defect. 

It results in death. 

Based upon appropriate medical judgment, it may jeopardize the subject’s health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in this 
definition.

It adversely affects the risk/benefit ratio of the study. 
An adverse event may be graded as severe but still not meet the criteria for a SAE. Similarly, an 
adverse event may be graded as moderate but still meet the criteria for an SAE. It is important for the 
PI to consider the grade of the event as well as its seriousness when determining whether reporting to 
the IRB is necessary. 
13.5.2.5
Plan for reporting adverse events

Reporting adverse events to the IRB
The investigator will report the following types of adverse events to the IRB: 
o
Serious AND unanticipated AND possibly, probably or definitely related events.
o
Anticipated adverse events occurring with a greater frequency than expected.
o
Other unanticipated problems involving risks to participants or others. 
These adverse events or unanticipated problems involving risks to participants or others will be 
reported to the IRB within 10 working days of becoming known to the investigator, using the 
appropriate forms found in IRB Manager.

Reporting adverse events to co-investigators
The following individuals and funding and/or regulatory agencies will be notified of adverse events: 
o
All co-investigators listed on the protocol. 
o
Study sponsor(s) – Pennington NORC.
o
National Institutes of Health. 
The Principal Investigator (Prachi Singh) and/or Medical Investigator (MI) (Kishore Gadde) will 
conduct a review of all adverse events upon completion of every study subject. The Principal 
Investigator will evaluate the frequency and severity of the adverse events and determine if 
modifications to the protocol or consent form are required. 
13.5.2.6
Surveillance Procedures
 Adverse events will be documented during the scheduled visits or during phone calls during off-
weeks. For each sign, symptom or adverse event, the following information will be recorded: 

A brief descriptor of the adverse event 

Start and stop dates 

Intensity (mild / moderate / severe) 

Whether the AE was “serious” or not (as defined below) 
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
Causal association with the intervention assigned (unrelated/ unlikely/ possible/ probable/ 
definite) 

Outcome (resolved / resolved with sequelae / improving / still present and unchanged / 
death) 

Action taken with respect to the intervention (none / intervention temporarily discontinued / 
medical therapy required / intervention permanently discontinued / other). 
Adverse event data will be collected from the date of consent until the final visit. Adverse event data will 
be analyzed quarterly, but serious or life-threatening adverse events may require immediate reporting and 
follow-up. We anticipate most adverse events will be mild and the subject will be able to resume activities 
within a day or two of reporting the event. 
13.6 Withdrawal of Participants
There is no risk associated with withdrawal from the study. Participants may be withdrawn from the study if 
either the PI or MI feels that their continued participation would jeopardize the participant’s health. In case of 
withdrawal, early termination procedures would be followed including documentation of adverse events, drug 
side effects, and reason for withdrawal. Any remaining study drug would also be collected at this time.
13.7 Stopping Rules
This study does not involve major risk for participating. Nevertheless, in addition to monitoring recruitment, 
we also will monitor the rates of adverse events in our participants. The study investigators will alert the IRB, if 
a larger than reasonably expected adverse event rate occurs in our participants.
13.8 Data Collection, Storage, and Confidentiality
13.8.1 Protection of Stored Data
Protection of subject privacy will be accomplished by a variety of stringent security measures. All 
medical records will be stored in locked areas, and access to these areas is limited to the clinic support 
staff, the Director of the clinical facilities, PIs at PBRC, and authorized designees of the PI. Volunteer 
medical records will be filed according to an assigned volunteer ID number. All forms on the chart, with the 
exception of the consent form, will display only the ID number, with no subject-identifiable information. All 
of these will be kept separate from records with names and other personal information. The only people 
who will know that these patients are research participants are members of the research team (including 
research collaborators). However, participant information will be shared with ApneaMed via prescription to 
obtain required PAP devices. No information about them, or provided by them during the research, will be 
disclosed to others without their written permission, except if it is necessary to protect their rights or welfare 
(for example, in case of injury or emergency care), or if it is required by law. When the results of the research 
are published or discussed in conferences, no information will be included that would reveal the identity of 
the individuals. Participants will be identified by codes when the data gathered in this procedure is presented 
or published. Authorized representatives of the NIH may need to review records of individual participants. 
As a result, they may see their name; but they are bound by rules of confidentiality not to reveal the 
participants’ identity to others. Electronic data storage is secured with password protection and similarly 
restricted with only the PI and authorized persons having access to databases containing confidential 
clinical records (i.e. those containing name, social security number, or other identifying information). 
Electronic communication will involve only unidentifiable information.                 
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13.8.2 Confidentiality
PBRC complies with the federal 1996 Health Insurance Portability and Accountability Act (HIPAA). 
Specifically, PBRC protects the privacy and confidentiality of medical records and information contained in 
medical records of persons who are participants of research projects, including all protected health 
information (PHI) as defined by the HIPAA privacy Regulations. PHI of research participants and the use or 
disclosure of such information is governed by PBRC research policies as well as Common Rule, FDA 
regulations, and other applicable laws. 
PBRC and study PI (the person chiefly responsible for the record) protect the privacy of research 
participants and their PHI collected during a research project. PBRC will not use or disclose existing PHI or 
PHI created during a research project, unless the:

Subject signs both (a) a HIPAA Authorization for use and disclosure of PHI using an approved 
Authorization Form or other form containing all the elements of legally effective HIPAA authorization; and (b) 
the informed consent to participate in research form approved by IRB; or

IRB grants a waiver to the requirement of obtaining a signed HIPAA authorization Form, or

IRB approved protocol uses properly de-identified PHI
All volunteers are assured of their anonymity and confidentiality both verbally and in the informed consent.
13.8.3 ClinicalTrials.gov Requirements
The clinical study is registered on ClinicalTrials.gov, in accordance with NIH recommendations. The 
unique NCT identifier (NCT04530747) will be included in all future Progress Reports and publications.
14 DATA MANAGEMENT AND ANALYSIS
All questionnaire data will be stored using REDCap. Other participant data will be stored on secured servers 
at Pennington Biomedical.
14.3 Data management
The data management will be conducted by the Pennington Biomedical Research Computing Group. There 
will be limited access to all data including locked cabinets for paper files and password protected computers 
for electronic data.
REDCap, a web-based application used to build and manage surveys and databases, will be used for 
questionnaire collection in this study. REDCap (Research Electronic Data Capture) is a secure, web-based 
application that is flexible enough to be used for a variety of types of research. REDCap provides an intuitive 
user interface that streamlines project development and improves data entry through real-time validation rules 
(with automated data type and range checks). REDCap also provides easy data manipulation (with audit trails 
for reporting, monitoring and querying patient records) and an automated export mechanism to common 
statistical packages (JMP, SPSS, SAS, Stata, R/S-Plus).
14.4 Statistical Plan: 
Statistical analyses will be performed by Dr. Robbie Beyl with support from the LA CaTS Center (U54-
GM104940) in accordance with a pre-specified statistical analysis plan.
14.4.1 Sample Size Considerations
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Although a formal power analysis was not feasible in this randomized, crossover pilot trial, we can 
expect significant improvements to be detectable with up to 18 completers for whole-body insulin sensitivity 
determined by Matsuda Index. Importantly, the proposed trial will be used to generate first-of-its-kind 
preliminary data for our investigative team to establish effect sizes and, therefore, develop power 
calculations as part of a future R01-level grant application. 
14.4.2 Statistical Analyses
The primary outcome is insulin sensitivity via Matsuda Index. We will use mixed effect linear models, 
accounting for correlation over time and treatment to assess outcome difference in metformin and placebo 
treated groups. Primary analysis will be conducted on all study participants who have taken one dose of 
the study drug and used CPAP for at least one night. Sensitivity analyses will be conducted on per-protocol 
sample of subjects adherent to the study interventions. Publications will acknowledge the limitation of small 
sample and any other weaknesses.
14.5 Data Sharing

With Collaborators: There are no plans for any data sharing. If needed, data sharing agreements will be 
put into place with the collaborators prior to any data transfer. All shared data will be de-identified and 
occur over a secure, encrypted network.

Sharing of Results with Participants: Clinically relevant incidental findings from questionnaires 
(excessive daytime sleepiness), overnight oximetry (risk for sleep apnea) and overnight sleep study will 
be shared with participants as determined by study MI.
15 REFERENCES 
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Dempsey JA, Veasey SC, Morgan BJ, O'Donnell CP. Pathophysiology of sleep apnea. Physiol Rev. 
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PMCID: 3970937.
2.
Drager LF, Togeiro SM, Polotsky VY, Lorenzi-Filho G. Obstructive sleep apnea: a cardiometabolic risk in 
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10.1016/j.jacc.2013.05.045. PubMed PMID: 23770180; PMCID: 4461232.
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Huang T, Lin BM, Stampfer MJ, Tworoger SS, Hu FB, Redline S. A Population-Based Study of the 
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30072403; PMCID: PMC6150434.
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Chasens ER, Strollo PJ, Jr. Treatment of obstructive sleep apnea on insulin resistance: not an "anti-sugar 
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PubMed PMID: 23607847.
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Mokhlesi B, Ayas NT. Cardiovascular Events in Obstructive Sleep Apnea - Can CPAP Therapy SAVE 
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27571490.
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Giannarelli R, Aragona M, Coppelli A, Del Prato S. Reducing insulin resistance with metformin: the evidence 
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PubMed PMID: 14502098.
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7.
Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a Tool to Target Aging. Cell Metab. 
2016;23(6):1060-5. doi: 10.1016/j.cmet.2016.05.011. PubMed PMID: 27304507; PMCID: PMC5943638.
8.
Kirkland JL, Tchkonia T. Cellular Senescence: A Translational Perspective. EBioMedicine. 2017;21:21-8. 
Epub 2017/04/19. doi: 10.1016/j.ebiom.2017.04.013. PubMed PMID: 28416161; PMCID: PMC5514381.
9.
Schafer MJ, Miller JD, LeBrasseur NK. Cellular senescence: Implications for metabolic disease. Mol Cell 
Endocrinol. 2017;455:93-102. Epub 2016/09/04. doi: 10.1016/j.mce.2016.08.047. PubMed PMID: 
27591120; PMCID: PMC5857952.
10.
Shroufi A, Powles JW. Adherence and chemoprevention in major cardiovascular disease: a simulation study 
of the benefits of additional use of statins. J Epidemiol Community Health. 2010;64(2):109-13. doi: 
10.1136/jech.2009.091033. PubMed PMID: 20056964.
11.
Iber C, Ancoli-Israel S, Chesson AL, Quan SF. The AASM manual for the scoring of sleep and associated 
events: rules, terminology and technical specifications. Westchester, Ill: American Academy of Sleep 
Medicine; 2007.
12.
Belfiore F, Iannello S, Camuto M, Fagone S, Cavaleri A. Insulin sensitivity of blood glucose versus insulin 
sensitivity of blood free fatty acids in normal, obese, and obese-diabetic subjects. Metabolism. 
2001;50(5):573-82. Epub 2001/04/25. doi: 10.1053/meta.2001.22518. PubMed PMID: 11319720.
13.
Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O, Bain J, Stevens R, Dyck JR, Newgard 
CB, Lopaschuk GD, Muoio DM. Mitochondrial overload and incomplete fatty acid oxidation contribute to 
skeletal 
muscle 
insulin 
resistance. 
Cell 
Metab. 
2008;7(1):45-56. 
Epub 
2008/01/08. 
doi: 
10.1016/j.cmet.2007.10.013. PubMed PMID: 18177724.
14.
Noland RC, Koves TR, Seiler SE, Lum H, Lust RM, Ilkayeva O, Stevens RD, Hegardt FG, Muoio DM. 
Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and 
metabolic control. J Biol Chem. 2009;284(34):22840-52. Epub 2009/06/26. doi: 10.1074/jbc.M109.032888. 
PubMed PMID: 19553674; PMCID: PMC2755692.
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CONSENT TO PARTICIPATE IN A RESEARCH STUDY
FOR AN ADULT
INFORMED CONSENT - PART I
Title of Study: Metabolic Effects of Metformin Therapy in Obstructive 
Sleep Apnea (METOSA)                                         
Study Sponsor: Pennington Biomedical Research Center 
 
Nutrition Obesity Research Center (NORC)                                        
Key Information

Why am I being asked to review this form?
o
You are being asked to take part in a research study. This form is provided so 
that you may read and understand the reasons why you might or might not 
want to participate in the research. Your participation is voluntary.

What is the purpose, duration, and procedures of this study?
o
The purpose of this research study is to compare the effects of metformin (a 
drug that prevents and treats diabetes) versus a placebo on metabolism in 
patients with obstructive sleep apnea using positive airway pressure (PAP) 
therapy. Metabolism is a process where your body converts what you eat and 
drink into energy that your body needs to function. For the purpose of this 
study, metformin is considered investigational, since it is not approved for use 
in patients with obstructive sleep apnea.
o
Your expected time in this study will be up to 4 months consisting of 6 study 
visits. 
o
The procedures involved in this study include:

Overnight sleep study

Standard treatment of obstructive sleep apnea using PAP

Taking metformin or placebo

Blood draws

Fat and muscle biopsy

Measurement of body composition 

Measurement of glucose metabolism

24 hour blood pressure monitoring

What are the possible risks and discomforts?
o
Metformin: There are some common side-effects related to metformin use 
including diarrhea, gas, and upset stomach. Uncommon or rare side effects 
might include metformin-associated lactic acidosis. This extremely rare side 
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effect may be severe enough to cause death, hypothermia, hypotension, and 
resistant bradyarrhythmias. We will not include you in this study if your chances 
to develop this rare side effect are high.
o
Fasting for 10 hours: There is a possibility that fasting for 10 hours may make 
you feel nauseous.
o
Blood draws: There is the possibility of infection and/or pain and bruising at 
the vein on your arm where the needle is inserted. Aseptic (sterile) technique 
and trained personnel minimize these risks.
o
Fat and muscle biopsies: Mild to severe pain, soreness, and bruising, and a 
small scar are common risks. There is a small risk of a hematoma (collection 
of blood in the tissue) or infection at the biopsy site. A sterile technique will be 
used to minimize these risks and the biopsy site will be monitored closely.
o
Body composition by DXA scan: The amount of radiation used for this 
procedure is very small. The radiation dose for this scan is equivalent to the 
radiation you are naturally exposed to in the environment in less than one day.
o
Glucose tolerance test: There is a possibility of pain, bruising, or infection at 
the site of the needle insertion for the IV line. Trained personnel minimize this 
risk. The glucose drink may cause nausea, vomiting, abdominal bloating, or a 
headache.
o
A more comprehensive and detailed description of reasonably foreseeable 
risks to subjects are included later in Section 6 of the informed consent.

What are the possible benefits?
o
We cannot promise any benefits from your being in the study. Your 
participation may help us gain knowledge that may help people in the future.

If you choose not to participate in the study, are there other choices?
o
You have the choice at any time not to participate in this research study. 
o
If you decide not to participate in this study, any health benefits to which you 
are entitled will not be affected in any way.
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Detailed Information
1- Who is doing the study?
     Investigator Information:
      Principal Investigator: Prachi Singh, Ph.D.
(225) 763-3151
      Medical Investigator:
Kishore Gadde, M.D. 
(225) 763-2552
24-hr. Emergency Phone Nos.:
(225) 763-2500 (Weekdays 7:00 a.m.-4:30 p.m.)
(225) 765-4644 (After 4:30 p.m. and Weekends)
      
Sub Investigator: 
Edward C. Mader, Jr., MD, FAASM
LSU Health Sciences Center – New Orleans
Department of Neurology
Dr. Prachi Singh directs this study, which is under the medical supervision of Dr. 
Kishore Gadde. We expect about 20 people from the greater Baton Rouge area will be 
enrolled in this study. The study will take place over a period of 1 year. Your expected 
time in this study will be up to 4 months.  
2- Where is the study being conducted? 
This study takes place at Pennington Biomedical Research Center in Baton Rouge, LA.
3- What is the purpose of this study?
The purpose of the study is to see if metformin improves metabolism in patients with 
obstructive sleep apnea (OSA) using positive airway pressure (PAP) therapy. 
Metformin is approved by the Food and Drug Administration (FDA) for the treatment and 
prevention of diabetes. It is not approved for use in patients with OSA.
4- Who is eligible to participate in the study?  
You may qualify for this study if you:

Are aged 35-65 years

Are not diabetic

Have a body mass index (BMI) between 30 and 50 kg/m2 (inclusive)

Have moderate to severe sleep apnea

Are willing to participate in study procedures including video recorded in-lab 
sleep studies, regular use of PAP therapy to treat OSA, and taking the study 
drug regularly)
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
Are willing to have fat and muscle tissue collected

Are willing to have blood, as well as fat and muscle tissue stored for future 
use

Are willing to use appropriate contraceptive to avoid pregnancy throughout 
the study, if needed.
You may not qualify for this study based on other eligibility criteria not listed. The study 
coordinator will go over this information in detail.
5- What will happen to you if you take part in the study?
Your participation in the study will last up to 4 months. If you agree to participate, you 
will be asked to come to Pennington Biomedical Research Center for two screening 
visits to determine if you are eligible to participate. The first screening visit will last for 
approximately 2 hours and the second screening visit will require an overnight stay for 
the sleep study. If you qualify and choose to participate, the study will include 4 study 
visits approximately one month apart. You will be provided with a positive airway 
pressure (PAP) therapy for treatment of sleep apnea. You will be allowed to keep the 
PAP equipment for continued use once your participation in the study is complete. You 
will also be asked to take a study drug, which we will provide to you, for the next 3 
months. The study drug will be either metformin or placebo.
The following table shows what will happen at each screening and study visit:
Table 1: Clinic Visits and Assessments
Study Visit
Assessment
Screening 
Visit 1
Screening 
Visit 2
#3
Baseline
#4
Month 1
#5
Month 2
#6
Month 3
Informed consent
X
Health questionnaire
X
Physical examination
X
Medication reporting
X
Blood pressure and heart 
rate
X
Weight and Height
X
Blood draw
X
X
X
Overnight oximetry (at 
home)
X
Overnight sleep study
X
Weight, waist, hip, neck 
measure
X
X
Glucose tolerance test
X
X
Urine Pregnancy testing (if 
needed)
X
X
Questionnaires
X
X
Dietary assessment (food 
record)
X
X
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Screening visit 1 (2 hours); Fasting (avoid food and drinks besides plain water for 
at least 10 hours before this visit):
You will be asked to come to Pennington Biomedical Research Center to complete this 
visit to determine if you are eligible to participate in this study. This visit will take 
approximately 2 hours. The following will happen during this visit:

Consent: The study will be explained and you will be asked to sign a form to 
show that you agree to participate. 

Health Questionnaire: You will be asked to answer questions related to your 
general health. 

Medication reporting: You will be asked about your current and most recent use 
of medicines and supplements.

Measurement of weight and height

Vital signs: Your blood pressure and heart rate will be obtained.

Blood draw: You will have a small amount of your blood drawn from your arm so 
that we can make sure you are healthy enough to participate in this study.

Oximetry: You will be given a device (oximeter) that attaches to your wrist and 
index finger and measures oxygen levels in your blood during sleep for one night. 
This tells us about your sleep quality. You will be provided with clear instructions 
on how and when to use the device. You will be asked to drop-off the device after 
you have recorded your sleep quality. If the data is incomplete, you may be 
asked to repeat this measure.
Screening visit 2 (overnight stay, 12 hours): If you qualify based on screening visit 1, 
you will be asked to come to Pennington Biomedical for an overnight visit to monitor 
your sleep after having dinner. You will be asked to avoid consuming any caffeine and 
alcohol at least 10 hours prior to this study visit. You will also be asked to avoid any 
vigorous physical activities for at least 10 hours prior to the study visit.

Sleep study: You will undergo an overnight sleep study where sticky patches will 
be applied to your head, chest, and legs, a loose band will be placed around your 
chest and stomach and you will be allowed to sleep in a dark, quiet room. Your 
sleep study will be video-recorded. We will then review the results of your sleep 
study and let you know if you have a sleep disorder. This test is only for research 
purpose.
Body composition (DXA)
X
X
Fat biopsy
X
X
Muscle biopsy
X
X
24 h blood pressure (at 
home)
X
X
Study drug provided
X
X
X
PAP provided
X
Side effects monitoring
X
X
X
PAP and study drug use 
monitoring
X
X
X
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
You will be woken up from sleep at 6:00 am and the wires and patches from the 
sleep study will be removed.
If you qualify based on this screening visit and are interested in participating:
You will complete 4 study visits over the coming 3 months. Additional visits may be 
required if you have difficulties with PAP treatment or study drug.
Study visit 1 (4 ½ hours); Fasting (avoid food and drinks besides plain water for 
at least 10 hours before this visit):
This visit will take approximately 4.5 hours. The following will happen during this visit

Measurement of weight 

Measurement of waist, hip, arm and neck circumference

If needed, you will be asked to provide a urine sample: Women of childbearing 
potential will be asked to provide a urine sample for a pregnancy test to make 
sure it is safe to continue in the study. 

Body composition measurement by DXA scan (about 10 minutes): This scan 
measures the amount of bone, muscle, and fat in your body. The scan will be 
performed using a whole-body scanner. You will be required to wear a hospital 
gown, to remove all metal-containing objects from your body, and to lie down on 
the table. You will be carefully positioned on the table, and your legs will be 
placed together using two Velcro straps. A scanner emitting low energy X-rays 
and a detector will pass along your body. You will be asked to remain completely 
still while the scan is in progress. The scan takes approximately ten minutes. 
This scan is for research purposes only and not for diagnostic treatment.

Oral glucose tolerance test (about 2 hours):  An IV line will be placed in your arm 
vein for blood draw purposes and will remain there throughout the testing. A 
blood sample will be drawn, and then you will drink a sugar solution consisting of 
75 grams of glucose. Blood will be drawn at specific times after you consume the 
drink. Each blood sample will be about 1 teaspoon. (5 tablespoons total for the 
test). During your IV procedure, a small amount of your own blood (less 
than 1 teaspoon) will immediately be returned into your vein through the IV 
after each specimen is collected. You will be provided lunch after the fasting 
procedures have been completed.

Fasting blood draw: Using the IV line placed on your arm for the oral glucose 
tolerance test we will draw approximately 1.5 tablespoon blood to be archived for 
future use.

Fat Biopsy: This procedure is used to sample fat cells from underneath the 
abdominal skin after cleansing the skin with iodine and using a local anesthetic. 
After cleansing the area, the doctor or nurse practitioner will make a small 
incision in the skin and introduce a needle under the skin to remove fat cells. 
About 1.5 to 2 grams (less than half a teaspoon size) of fat will be removed. After 
the biopsy is completed, the skin will be held closed with a sterile adhesive 
bandage; an antibiotic ointment will be applied.

Muscle Biopsy: This procedure is used to sample muscle cells from underneath 
the skin of the leg. After cleaning the skin with iodine and using a local 
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anesthetic, the doctor or nurse practitioner will make a small incision in the skin 
and introduce a needle under the skin to remove muscle cells. About 500 
milligrams (less than a teaspoon size) of muscle will be removed. After the 
biopsy is completed, the skin will be closed with a sterile adhesive bandage and 
an antibiotic ointment will be applied.

Blood Pressure Monitoring: You will be given an ambulatory blood pressure 
monitor to wear for the next 24 hours. This procedure records your blood 
pressure and heart rate. You will wear a device the size of a small camera 
connected to a blood pressure cuff on your arm for 24 hours. The cuff of this 
device inflates automatically every 30 minutes during the day and night. Upon 
inflation, the device will make a quiet noise and will cause pressure on your arm. 
At the end of the 24 hours, you will return to the clinic to return the monitor. 
Depending upon the amount of data collected, you may be asked to wear the 
monitor for an additional day.  

Sleep quality and physical activity survey: You will be asked to fill out a few brief 
surveys about your habitual sleep and physical activity. 

3-day dietary record: You will be asked to record your food and drink intake for 
three non-consecutive days including one weekend day. Detailed instructions to 
fill the daily log will be provided.

Positive Airway Pressure (PAP) therapy: We will provide you with detailed 
instructions on how to use PAP equipment for sleep apnea treatment. The device 
is designed to keep the airway open while a person sleeps by gently pressurizing 
the air that they breathe. You will be encouraged to use PAP daily for the entire 
sleep duration. We will monitor your PAP usage during the study duration and 
will contact you if the PAP usage is not ideal. 

Study drug: We will assign you by chance (like a coin toss) to metformin or the 
placebo group. Neither you or the Principal Investigator can choose your study 
group. You will have an equal chance of being assigned to the metformin group. 
This study uses a placebo. A placebo looks exactly like the study drug, but it 
contains no active ingredient. We use placebos in research studies to learn if the 
effects seen in research participants are truly from the study drug. You and the 
Principal Investigator will not know which study drug (metformin or placebo) is 
being given to you. However, in case of an emergency, this information will be 
available.
o
You will be provided the study drug along with detailed instructions for 
how and when to take the capsule. Each capsule will contain either 500 
mg of metformin or 500 mg of placebo. You will be asked to take one 
capsule daily for the 1st week, 2 capsules daily for the 2nd week, 3 
capsules daily for the 3rd week, and 4 capsules daily for the 4th week until 
the end of the study. We will also tell you about the potential side effects 
and reactions.
o
You will be asked to stop taking the study drug and to contact the study 
team within 24 hours if you feel cold in your hands or feet, feel dizzy or 
lightheaded, feel weak or tired, have a slow or irregular heartbeat, have 
unusual (not normal) muscle pain, have trouble breathing, or feel 
unusually sleepy or drowsy. 
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o
During the study, we will ask you that you do not change any medication 
or supplements that you may be taking prior to the start of the study. The 
study team needs to be informed promptly of any planned changes in 
medications. The study team will decide if these changes will prevent you 
from continuing participation in the study.
Study visit 2 (45 minutes): (within 25 to 30 days of visit 1)
This visit will take approximately 45 min. You will be asked to bring the bottle of study 
drug for this visit. The following will happen during this visit

Study drug: We will ask you questions to find out if you may have experienced 
any side effects related to study drug. We will provide you study drug for the next 
month.

PAP use: We will check how often you use PAP and provide advice if needed.
Study visit 3 (45 minutes): (within 25 to 30 days of visit 2)
This visit will take approximately 45 min. You will be asked to bring the bottle of study 
drug for this visit and all measures for visit 2 will be repeated. 
Study visit 4 (4 ½ hours); Fasting (avoid food and drinks besides plain water for at 
least 10 hours before this visit): (within 25 to 30 days of visit 3)
This visit will take approximately 4.5 hours. All procedures from study visit 1 will be 
repeated and an additional 1 tablespoon of blood will be drawn for routine health check 
at this visit. We will also ask you questions to find out if you may have experienced any 
side effects related to study drug and any remaining study capsules will be returned to 
study staff. 
The study will end after the blood pressure monitor has been returned.
6- What are the possible risks and discomforts?
Study Procedures

Fasting for 10 hours: There is a possibility that fasting for 10 hours may make 
you feel nauseous. Light snacks will be provided for you to eat once the fasting 
procedures are completed.

Surveys/Questionnaires: You do not have to answer any questions you do not 
want to answer.

Blood Draws: There is the possibility of infection and/or pain and bruising at the 
vein on your arm where the needle is inserted. Aseptic (sterile) technique and 
trained personnel minimize these risks. 

Overnight Oximetry: There are no significant risks related to overnight oximetry 
other than temporary discomfort while wearing the device.

Overnight Sleep study: You may have some discomfort with the application of 
the electrodes to your scalp. You may also experience some claustrophobia 
because of the monitoring equipment that is applied to your head and face. It is 
also possible that you may wake up at night feeling a little disoriented. To obtain 
the polysomnographic measurements, it may be necessary to glue many small 
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wires on your scalp and face. The adhesive used to attach these wires has a 
strong smell, and you may feel a scratching sensation when the wires are 
applied.

Oral glucose tolerance test: There is a possibility of pain, bruising, or infection 
at the site of the needle insertion for the IV line. Trained personnel minimize this 
risk. The drink may make cause nausea, vomiting, abdominal bloating, or a 
headache.  

Fat Biopsy: Mild to severe pain, soreness, and bruising, and a small scar are 
common risks. There is a small risk of a hematoma (collection of blood in the 
tissue) or infection at the biopsy site. Sterile technique will be used to minimize 
these risks and the biopsy site will be monitored closely.

Muscle Biopsy: Mild to severe pain, soreness, bruising, and a small scar are 
common risks. There is a small risk of a hematoma (collection of blood in the 
tissue) or infection at the biopsy site. There is a slight risk that a superficial nerve 
may be cut; the nerve may heal, or it may result in a permanent loss of sensation 
in the skin at the biopsy site. 

Body Composition by DXA Scan: The amount of radiation used for this 
procedure is very small. The radiation dose for this scan is equivalent to the 
radiation you are naturally exposed to in the environment in less than one day. 
Scans will not be performed on any subject who is pregnant. A pregnancy test 
will be performed within 72 hours before the scan on females of child-bearing 
potential. 
o
Lifetime radiation exposure: We are exposed to radiation in the environment 
on a daily basis; however, some scientists have suggested that humans 
have a lifetime maximum exposure limit. Exposure to radiation is not without 
risk, but it is difficult to quantify the exact amount someone is exposed to. By 
participating in this study you will be exposed to radiation that will add to this 
lifetime maximum exposure limit. If you believe you have been exposed to a 
significant amount of radiation as part of your occupation or due to treatment 
for a specific medical condition, you should notify the study team to discuss 
whether or not this study would be appropriate for you.

Blood Pressure Monitoring: There are no known risks associated with the 
blood pressure monitor. You may experience some discomfort having the cuff 
inflate every 30 minutes around the clock.

Metformin: The most common side effects of metformin include nausea, 
headaches, diarrhea, vomiting, bloating, excessive gas, loss of appetite, and an 
unpleasant taste in the mouth. These are more common when the medication is 
first started and lessen or disappear over time. About 10 out of 100 people using 
metformin may experience these symptoms to some degree. However, these 
side effects are rarely severe enough to result in needing to stop the medication. 
Other side effects include lower-than-normal levels of vitamin B12 in the blood, 
which may rarely lead to anemia (low blood count), although it is unlikely to 
happen in this study because of the short duration of treatment. Hypoglycemia 
(low blood sugar) rarely occurs when metformin is taken by itself, but it can occur 
when metformin is combined with some other diabetes medications.
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In very rare instances (fewer than 3 in 100,000), a condition called lactic acidosis 
has been reported in patients taking metformin. When lactic acidosis occurs, it is 
usually in persons who have other severe medical problems, such as kidney 
disease, liver disease, or severe circulatory problems. We will analyze your blood 
and ask you about symptoms to make sure it is safe for you to take this 
medication. In addition, you must notify the study team immediately if you 
experience any of the following symptoms which could be signs of lactic acidosis: 
feeling cold in your hands or feet, feeling dizzy or lightheaded, feeling weak or 
tired, having a slow or irregular heartbeat, having unusual (not normal) muscle 
pain, having trouble breathing, or if you feel unusually sleepy or drowsy.
You should talk to the study team before you undergo any surgery, X-ray 
procedures, or CT scans that use any type of injection (such as dye that makes 
X-rays easier to see), as you will need to stop taking your study drug during the 
time of the procedure. Alcohol should not be used in excess while taking 
metformin. Inform your study doctor if you currently have (or develop during the 
course of the trial) kidney or liver disease, heart failure or severe infections.

Confidentiality of Data: Taking part in this research may involve providing 
information that one considers confidential or private. Our staff are trained in how 
to maintain your confidentiality but there is a slight risk that data could be 
revealed inappropriately or accidentally.
Unforeseeable Risks Involving Pregnant Women
If you are pregnant or become pregnant, metformin may involve risks to the embryo or 
fetus, which are currently unforeseeable.
Will I be notified if my blood draws, DXA scan, sleep study or blood pressure 
result(s) in an incidental finding?
During a research study, a researcher may notice something that he or she was not 
looking for. This is called an “incidental” or “unexpected” finding. These incidental 
findings are not directly related to the research. However, they may show important 
information about the health of a research volunteer.
Researchers may share some or all of their findings with you. However, you may not 
learn about any findings for a very long time. If such findings occur, you will be notified 
by the medical investigator or trained study personnel and referred to a treatment facility 
for further testing and/or treatment. 
Risks: It can be very upsetting to learn unexpected information about your health. This 
is especially true if you learn that you have or will develop a condition that has no 
treatment or cure. There is a chance that unexpected findings could affect your family or 
social relationships, change your family planning decisions, or affect you financially. You 
might need more tests and procedures to find out what the information really means. It’s 
also possible that the information might be incorrect, so you would worry without cause.
Unknown Risks
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In addition to the risks listed above, you may experience a previously unknown risk or 
side effect.  
7- What are the possible benefits?
We cannot promise any benefits from your being in the study. If you take part in this 
study, you may help others in the future.
8- If you do not want to take part in the study, are there other 
choices? 
You have the choice at any time not to participate in this research study. If you choose 
not to participate, any health benefits to which you are entitled will not be affected in any 
way. You have the right to take part now and change your mind later on.
9- If you have any questions or problems, whom can you call?
If you have any questions about your rights as a research volunteer, you should call the 
Institutional Review Board Office at 225-763-2693 or the Executive Director of 
Pennington Biomedical at 225-763-2513. If you have any questions about the research 
study, contact Dr. Prachi Singh at 225-763-3151. If you think you have a research-
related injury or medical illness, you should call Dr. Kishore Gadde at 225-763-2552 
during regular working hours. After working hours and on weekends you should call the 
answering service at 225-765-4644. The on-call physician will respond to your call.
10- What information will be kept private?
Your sleep study data will be sent to researchers and vendors outside of the Pennington 
Biomedical Research Center. The data that are sent to these researchers may contain 
identifiable information. Identifiable information is being sent to these researchers and 
vendors because based on this information, they will be able to provide PAP 
prescription and equipment.
Every effort will be made to maintain the confidentiality of your study records. However, 
someone from the National Institutes of Health, the Pennington Biomedical Research 
Center, Louisiana State University or the sponsor may inspect and/or copy the medical 
records related to the study. Results of the study may be published; however, we will 
keep your name and other identifying information private. Other than as set forth above, 
your identity will remain confidential unless disclosure is required by law.
Identifiable Private Information or Identifiable Biospecimens 
Any identifiers might be removed from your identifiable information or identifiable 
biospecimens and that, after such removal, the information or biospecimens could be 
used for future research studies or given to another investigator for future research 
without additional informed consent from the subject or legally authorized 
representative. 
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A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This web site will not include information that can identify you. At 
most, the web site will include a summary of the results. You can search this web site at 
any time.
Biospecimens and Commercial Profit 
Your blood, fat and muscle samples may be used to develop new drugs or other 
products that may result in commercial profit that will not be shared with you.
Whole Genomic Sequencing
Your blood, fat, and muscle samples collected for this research will be analyzed for the 
study. As part of the analysis, the research might include exome sequencing. This 
means that the researchers might look at your sample to learn about your genes (DNA). 
There are different ways to look at your DNA. Researchers often use a technology 
called sequencing to look at your DNA. Sequencing “reads” each letter of the DNA and 
finds changes (also called “variations” or “mutations”) in your genes that may cause 
disease or affect how your body reacts to a certain disease. Cell lines are living tissue 
samples that can be grown in a laboratory. A cell line can provide an unlimited supply of 
cells in the future without asking for more samples from you. Each cell contains your 
complete DNA.
Genetic Information
The Genetic Information Nondiscrimination Act (GINA) may help protect you from health 
insurance or health-related employment discrimination based on genetic information.  
The law provides that health insurance companies and group health plans 

may not ask for genetic information from this research and 

may not use genetic information when making decision about eligibility or 
premiums
The law will not stop health insurance companies from using genetic information to 
decide whether to pay claims. The law does not apply to other types of insurance (such 
as life, disability or long-term care). 
Despite the GINA protections and the best efforts of the research team to protect your 
information, you may still be at risk if information about you were to become known to 
people outside of this study.
11- Can your taking part in the study end early?
Dr. Prachi Singh, Dr. Kishore Gadde, or the study sponsor can withdraw you from the 
study for any reason or for no reason. Possible reasons for withdrawal include 
emergence of significant safety concerns which, in the opinion of the investigator, 
warrants withdrawal or significant change in medications while participating in the study. 
The sponsor of the study may also end the study early.  
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If your participation in the research ends early because of the investigator or by your 
choice or a reason listed above, termination procedures may need to be completed or 
follow-up data may need to be obtained to ensure your safety. These procedures 
include returning study drug and providing information related to side effects faced and 
reason for withdrawal. The study staff will go over the details with you. 
You may withdraw from the study at any time without penalty; however, information 
Pennington Biomedical has previously collected cannot be removed from the study. 
 
If you decide you would like to withdraw your consent, you must provide a written 
request to the Principal Investigator at:
Dr. Prachi Singh
Pennington Biomedical Research Center
6400 Perkins Road
Baton Rouge, LA 70808
12- What if information becomes available that might affect your 
decision to stay in the study?
Significant New Findings
During the course of this study there may be new findings from this or other research 
which may affect your willingness to continue participation. Information concerning any 
such new findings will be provided to you.
Clinically Relevant Research Results
In this study, you will be informed of any clinically relevant research results, including 
your individual results that may be discovered. These include your risk for sleep 
disorders and high blood pressure. 
13- What charges will you have to pay?
None 
14- What payment will you receive?
If you agree to take part, we will compensate you up to $300 upon completion of the 
study. If you do not complete the entire study, you will be compensated $100 for 
completing the first study visit, $25 each for completing the second and third study visit, 
and $150 for completing the final visit (Visit 4). You will also be allowed to keep the PAP 
equipment once the study has ended for continued OSA treatment. However, you will 
need to follow-up with your primary care provider for continued clinical care.
You will not be compensated for any screening visits. Your check will be requested from 
the LSU payroll department when you complete the study or at the appropriate 
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milestone if you are compensated during the course of the study. It usually takes about 
3-4 weeks for it to arrive at Pennington Biomedical Research Center.
U.S. citizens, legal resident aliens, and those who have a work eligible visa will need to 
provide their social security number to receive payment. 
You are subject to a 1099 for receiving compensation. Payments in excess of $600 per 
calendar year are considered taxable income. If you will be paid more than $600, 
Pennington Biomedical/LSU will report this income to the IRS.
Non-US citizens are subject to having taxes withheld from payment and will need a 
passport, visa and 1-94 for payment to be processed.   
I authorize that all information provided on this Informed Consent form and HIPAA 
Authorization form, including any and all personal and financial data may be shared with 
the Internal Revenue Service (IRS) for tax reporting. This data will be securely retained 
indefinitely. 
15- Will you be compensated for a study-related injury or medical 
illness?
No form of compensation for medical treatment or for other damages (i.e., lost wages, 
time lost from work, etc.) is available from the Pennington Biomedical Research Center. 
In the event of injury or medical illness resulting from the research procedures in which 
you participate, you will be referred to a treatment facility. Medical treatment may be 
provided at your expense or at the expense of your health care insurer (e.g., Medicare, 
Medicaid, Blue Cross-Blue Shield, Dental Insurer, etc.) which may or may not provide 
coverage. The Pennington Biomedical Research Center is a research facility and 
provides medical treatment only as part of research protocols. Should you require 
ongoing medical treatments, they must be provided by community physicians and 
hospitals.  
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16- Signatures  
By signing this consent form, I agree to participate in the study as it is described. The 
study has been discussed with me and all my questions have been answered. I 
understand that additional questions regarding the study should be directed to the study 
investigators. I agree with the terms above and acknowledge that I will be given a copy 
of this signed consent form. 
With my signature, I also acknowledge that I have been given either today or in the past 
a copy of the Notice of Privacy Practices for Protected Health Information.
        
Printed Name of Volunteer
                
Signature of Volunteer
    
Date
Printed Name of Person Administering Informed Consent
Signature of Person Administering Informed Consent              
Date                                               
Prachi Singh, PhD                            
Principal Investigator
Kishore Gadde, MD                                          
Medical Investigator
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17- What you need to know about future research with your 
biospecimens or imaging.  
This research study will store some of your blood, as well as fat and muscle tissue 
samples to be used for research at a later time. These bodily materials are called 
biospecimens. The storing of biospecimens in this study is not optional. If you do not want 
your biospecimens stored for future research, you may not participate in this study. 
Research with your biospecimens can help to find out more about understanding the 
causes of obesity, diabetes, cardiovascular disease, cancer, and dementia in patients 
with sleep apnea. 
Your blood, fat and muscle tissue samples may be sent to researchers outside of the 
Pennington Biomedical Research Center. Any personal information that could identify 
you will be removed before the samples are shared.
Your sleep study data will be sent to researchers and vendors outside of the Pennington 
Biomedical Research Center. The data that are sent to these researchers may contain 
identifiable information. Identifiable information is being sent to these researchers and 
vendors because based on this information, they will be able to provide PAP 
prescription and equipment.
What you should know about your biospecimens:

The samples will be stored indefinitely. 

If you agree to have your samples stored, you can change your mind later.

For privacy and confidentiality, your samples will be labeled with a unique series 
of letters and numbers. Pennington Biomedical will store your samples with this 
unique identifier and the minimum number of personal identifiers to meet 
laboratory standards. 

The future research may or may not take place at Pennington Biomedical and 
may or may not involve Pennington Biomedical Researchers.  

You will not be compensated for any research studies that might be conducted in 
the future.

You will not be informed of the details of any specific research studies that might 
be conducted in the future.

The collection of samples may give scientists valuable research material that can 
help them to develop new diagnostic tests, new treatments, and new ways to 
prevent diseases. 

The research done with your specimens may also help to develop new products 
in the future, or may be used to establish a cell line or test that could be patented 
or licensed. You will not receive any financial compensation for any patents, 
inventions, or licenses developed from this research.
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Withdrawal of Consent 
If you decide you would like to withdraw your consent, you must provide a written 
request to the Principal Investigator as outlined in Section 11 of this consent form. 
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