Effects of GLP-l Receptor Agonists on Cardiometabolic Alterations in HIV-associated Lipohypertrophy
Phase: PHASE2
Conditions: HIV/AIDS, Lipohypertrophy, Obesity
Sponsor: Case Western Reserve University

  
 
 
Effects of GLP-l Receptor Agonists on Cardiometabolic 
Alterations in HIV-associated Lipohypertrophy 
 
Protocol Number: GLP1RA-HIV-LH 
National Clinical Trial (NCT) Identified Number:  04019197 
Principal Investigators: Grace McComsey MD, Allison Eckard MD 
 
 
 
Principal Investigators:  
 
Grace A McComsey, MD, FIDSA  
Associate Chief Scientific Officer, University Hospitals Health System 
Director, UH Clinical Research Center 
Director, Dahms Clinical Research Unit 
John Kennell Endowed Chair 
Chief, Pediatric Infectious Diseases, and Rheumatology 
Professor of Pediatrics and Medicine 
Case Western Reserve University 
216-844-5936 
 
Allison Ross Eckard, MD, FIDSA, AAHIVS 
Associate Professor of Pediatrics and Medicine 
Divisions of Infectious Diseases  
Medical University of South Carolina 
135 Rutledge Ave, Ste 1217 
Charleston, SC 29425-7520 
Telephone 843-876-1920 
Fax 843-792-6680 
 
 
 
 
 
 
 
 
 
 
 

  
 
 
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 4 
1. 
PROTOCOL SUMMARY ............................................................................................................................... 5 
1.1 
Synopsis ................................................................................................................................................ 5 
1.2 
Schema ................................................................................................................................................. 6 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 7 
2 
INTRODUCTION ............................................................................................................................................ 8 
2.1 
Study Rationale .................................................................................................................................... 8 
2.2 
Background........................................................................................................................................... 8 
2.3 
Risk/Benefit Assessment .................................................................................................................. 13 
2.3.1 
Known Potential Risks ................................................................................................... 13 
2.3.2 
Known Potential Benefits .............................................................................................. 14 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 14 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 18 
4 
STUDY DESIGN ........................................................................................................................................... 20 
4.1 
Overall Design .................................................................................................................................... 20 
4.2 
Justification for Dose ......................................................................................................................... 21 
4.3 
End of Study Definition ..................................................................................................................... 21 
5 
STUDY POPULATION ................................................................................................................................ 22 
5.1 
Inclusion Criteria ................................................................................................................................ 22 
5.2 
Exclusion Criteria ............................................................................................................................... 24 
5.3 
Lifestyle Considerations .................................................................................................................... 25 
5.4 
Screen Failures .................................................................................................................................. 25 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 25 
6 
STUDY INTERVENTION ............................................................................................................................ 29 
6.1 
Study Intervention(s) Administration ............................................................................................... 29 
6.1.1 
Study Intervention Description ..................................................................................... 29 
6.1.2 
Dosing and Administration ............................................................................................ 29 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 30 
6.2.1 
Acquisition and accountability ...................................................................................... 30 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 30 
6.2.3 
Product Storage and Stability ....................................................................................... 30 
6.2.4 
Preparation ...................................................................................................................... 30 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 31 
6.4 
Study Intervention Compliance ........................................................................................................ 31 
6.5 
Concomitant Therapy ........................................................................................................................ 31 
6.5.1 
Rescue Medication ........................................................................................................ 31 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 32 
7.1 
Discontinuation of Study Intervention ............................................................................................. 32 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 32 

  
 
 
7.3 
Lost to Follow-Up ............................................................................................................................... 32 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 33 
8.1 
Efficacy Assessments ....................................................................................................................... 33 
8.2 
Safety and Other Assessments ....................................................................................................... 37 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 38 
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 38 
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 38 
8.3.3 
Classification of an Adverse Event .............................................................................. 38 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 35 
8.3.5 
Adverse Event Reporting .............................................................................................. 40 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 40 
8.3.7 
Reporting Events to Participants ................................................................................. 40 
8.3.8 
Events of Special Interest ............................................................................................. 41 
8.3.9 
Reporting of Pregnancy ................................................................................................ 41 
8.4 
Unanticipated Problems .................................................................................................................... 41 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 41 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 42 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 42 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 43 
9.1 
Statistical Hypotheses ....................................................................................................................... 43 
9.2 
Sample Size Determination .............................................................................................................. 43 
9.3 
Populations for Analyses .................................................................................................................. 43 
9.4 
Statistical Analyses............................................................................................................................ 44 
9.4.1 
General Approach .......................................................................................................... 44 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 44 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 45 
9.4.4 
Safety Analyses .............................................................................................................. 45 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 45 
9.4.6 
Planned Interim Analyses ............................................................................................. 45 
5 
9.4.7 
Tabulation of Individual participant Data .................................................................... 46 
9.4.8 
Exploratory Analyses ..................................................................................................... 46 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 47 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 47 
10.1.1 
Informed Consent Process ........................................................................................... 47 
10.1.2 
Study Discontinuation and Closure ............................................................................. 48 
10.1.3 
Future Use of Stored Specimens and Data ............................................................... 43 
10.1.4 
Key Roles and Study Governance .............................................................................. 49 
10.1.5 
Safety Oversight ............................................................................................................. 49 
10.1.6 
Clinical Monitoring .......................................................................................................... 50 
10.1.7 
Quality Assurance and Quality Control ....................................................................... 45 

  
 
 
10.1.8 
Data Handling and Record Keeping ............................................................................ 51 
10.1.9 
Protocol Deviations ........................................................................................................ 51 
10.1.10 
Publication and Data Sharing Policy ........................................................................... 51 
10.1.11 
Conflict of Interest Policy .............................................................................................. 52 
10.2 
Additional Considerations ................................................................................................................. 47 
10.3 
Abbreviations ...................................................................................................................................... 52 
10.4 
Protocol Amendment History ........................................................................................................... 54 
11 
REFERENCES ............................................................................................................................................. 49 
 

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STATEMENT OF COMPLIANCE 
 
The trial will be conducted in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), and the National 
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) terms and Conditions of Award. The 
Principal Investigators will assure that no deviation from, or changes to the protocol will take place 
without prior agreement from the Investigational New Drug (IND) or Investigational Device Exemption 
(IDE) sponsor, funding agency and documented approval from the Institutional Review Board (IRB), except 
where necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in 
the conduct of this study have completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval.  Approval of both the protocol and the consent form must 
be obtained before any participant is enrolled.  Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study.  All changes to the consent form 
will be IRB approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent, using a previously approved consent form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.  
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Effects of GLP-l Receptor Agonists on Cardiometabolic Alterations in HIV-
associated Lipohypertrophy 
Study Description: 
In this study, we will conduct a randomized, double-blinded, placebo-
controlled trial to assess the effect of GLP-1 receptor agonist (semaglutide) 
on visceral and ectopic fat, insulin resistance, inflammation markers, and 
the downstream effect on cardiovascular risk in HIV-infected individuals.  
Objectives: 
 
Primary Objective:  To characterize the effects of semaglutide on visceral 
and ectopic fat and elucidate potential mechanisms by which these effects 
occur in HIV-infected individuals with lipohypertrophy.  
 
Secondary Objectives: To examine the effect of semaglutide on lean body 
mass, inflammation, immune activation, gut integrity, and cardiovascular 
disease risk in HIV-infected individuals with lipohypertrophy and assess the 
sustainability of semaglutide effects after treatment discontinuation. 
 
 
Endpoints: 
Primary Endpoints: Visceral and ectopic fat changes at 32 weeks. 
Secondary Endpoints: Changes in lean body mass, markers of 
inflammation, immune activation, gut integrity, and cardiovascular disease 
assessment after 32 weeks of treatment and changes in outcomes 24 
weeks after treatment discontinuation (at 56 weeks).   
Study Population: 
104 HIV-infected individuals with lipohypertrophy  
 
Participants from all ethnic, racial, and sex/gender categories will be 
eligible and included, with the goal of an equal proportion of males and 
females and half minority populations. 
Phase: 
2b 
Description of 
Sites/Facilities Enrolling 
Participants: 
 
 
Participants will be enrolled at the HIV clinic at Case Western Reserve 
University in Cleveland, OH.  
Description of Study  
Intervention: 
Semaglutide 1.0 mg given by subcutaneous injection once weekly, or 
matching placebo, for 32 weeks. 
Study Duration: 
5 years. 
Participant Duration: 
56 weeks. 
 
 
1.2 
SCHEMA 
 
 
 
 

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1.3 
SCHEDULE OF ACTIVITIES (SOA) 

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2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Despite the advent of safer antiretroviral therapy agents with low potential for mitochondrial toxicity, 
lipohypertrophy (accumulation of central and ectopic fat) remains a common and significant challenge 
facing HIV providers and threatens the well-being of individuals living with HIV. Limited progress has been 
made in understanding and managing lipohypertrophy. Initially linked to the use of protease inhibitors 
(PIs), we have recently reported similar gains in peripheral and central fat after initiation of successful HIV 
treatment with both PIs and integrase inhibitors. These observations have challenged current beliefs and 
raised the concerns that fat accumulation may indeed be due to HIV itself, directly and/or indirectly, 
through the heightened inflammatory state that accompanies HIV. The role of alteration in gut hormone 
secretion and in gut epithelial barrier dysfunction in HIV-associated metabolic disorders is largely 
unknown, but it is plausible since chronic inflammation (such as that seen in HIV) has been shown to affect 
gut hormone secretions and gut integrity markers.  

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Studies of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in diabetics have shown them to be safe, 
well-tolerated, with very low to no concerns about drug-drug interactions, and, importantly, have caused 
weight loss that occurs preferentially via losses in visceral fat. Some GLP-1RAs have even shown to 
decrease clinical CVD events in diabetics. Thus, this promising class of drugs may offer a powerful tool to 
fight the triple threat facing the success of long-term HIV treatment: namely, 1) excess fat accumulation 
and ectopic fat deposition, 2) insulin resistance and a high prevalence of diabetes, and 3) endothelial 
dysfunction and cardiovascular disease (CVD) risk. GLP-1RAs act by partially-delineated mechanisms, 
several of which will be studied in this proposal. 
We will conduct a randomized, double-blinded, placebo-controlled clinical trial to assess whether a potent 
and safe GLP-1RA may positively affect visceral fat and ectopic fat accumulation, insulin resistance, 
inflammation markers, and the downstream effect on CVD in people living with HIV. 
 
 
2.2 
BACKGROUND  
Significance of the trial:  
Body composition alterations in HIV: Despite new, safer antiretroviral therapy (ART), certain aspects of 
adipose tissue alterations, previously termed “lipodystrophy,” continue to frequently occur in HIV-1. With 
older ART, specifically, thymidine nucleoside reverse transcriptase inhibitors (NRTIs), fat abnormalities 
were dominated by lipoatrophy, a devastating loss of fat from limbs and face that subsequently was linked 
by us and others to mitochondrial toxicity.1-3 Subsequent avoidance of these NRTIs led to an abrupt 
decrease in the incidence of lipoatrophy.4,5 However, the other facet of fat alterations, namely 
lipohypertrophy (or abdominal visceral fat accumulation), frequently associated with insulin resistance 
and ectopic fat deposition in the liver and pericardial regions, continues to be very prominent and a 
substantial threat to the success of ART. That is, these fat alterations not only cause major cosmetic 
concerns, but they are also associated with heightened inflammation and increased risk of cardiovascular 
disease (CVD).6 Initially thought to be linked to the use of protease inhibitors (PIs), we recently showed 
that subjects initiating therapy with integrase inhibitors (INSTI) suffered the same extent of visceral fat 
accumulation when compared to subjects initiating PI-based therapies (see preliminary data section).7 
Moreover, we recently showed that the odds of severe weight gain (generally defined as gains of ≥10% in 
weight over 96 weeks after ART initiation) were higher when subjects initiated HIV therapy with INSTI 
versus PIs.8 In these studies, we also showed that viral load prior to ART initiation was a main independent 
predictor of fat gain, in that subjects starting therapy with an HIV-1 RNA >100,000 copies/mL (or in a high 
viral load stratum) experienced 2 to 3 times the fat gain of those starting at a lower viral load, regardless 
of the ART drug class. In addition, levels of inflammatory markers such as interleukin-6 (IL-6) were 
positively correlated with total fat changes. These studies illustrate the fact that lipohypertrophy remains 
an important issue for people living with HIV (PLWH) and that HIV-related factors are important 
determinants of these fat alterations.  
Ectopic fat depots: Besides visceral fat accumulation, ectopic lipid deposition has been implicated in the 
pathophysiology of insulin resistance and obesity-related disorders. Hepatic fat is strongly correlated with 
the amount of visceral adipose tissue (VAT) in a prediabetic population9 and has been associated with CVD 
independent of classical risk factors.10 Cardiac ectopic fat can secrete cytokines like other visceral fat and 
may contribute to detrimental cardiac remodeling.11-13 In fact, epicardial fat (adipose tissue located 
between the myocardium and the visceral pericardium; also known as the visceral pericardium) has been 
shown to contain more mRNA and protein for IL-1β, IL-6, monocyte chemoattractant protein-1, and TNF-

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α than subcutaneous adipose tissue (SAT), and cytokine concentrations are significantly correlated with 
the accumulation of inflammatory cells, such as T-lymphocytes and macrophages.14,15 Ectopic cardiac fat 
volume represents a novel marker of CVD risk.16 In fact, pericardial fat volume actually is better correlated 
with coronary calcifications than VAT.17 We have shown that in PLWH on ART, pericardial fat was 
associated with insulin resistance (independent of VAT) and with the presence of coronary 
calcifications.18,19 
Management of lipohypertrophy in HIV:  A challenge in the modern treatment era: The mechanism and 
management of lipohypertrophy continue to present major challenges to HIV providers and PLWH. Diet 
and exercise have not been successful at reversing fat accumulation, nor were switches between different 
ART classes. Currently one medication, the growth hormone-releasing hormone, tesamorelin, is FDA-
approved specifically for the treatment of lipohypertrophy in HIV; however, it is not widely used due to 
its high cost, the transient nature of the improvement in fat (which returns to baseline after 
discontinuation of the drug), and the concern about worsening insulin resistance. The FDA also warns that 
the long-term cardiovascular safety and potential long-term CVD benefit are currently unknown. Lastly, 
tesamorelin does not significantly decrease weight, a downside in the current obesity epidemic, which 
includes PWLW.20 Thus, novel therapeutic interventions that could decrease weight, attenuate VAT 
accumulation, and potentially improve CVD risk are urgently needed.  
GLP-1RA: a multifaceted approach to treat cardiometabolic abnormalities in HIV: Glucagon-like peptide-
1 (GLP-1) is a naturally-occurring neuropeptide and an incretin secreted from intestinal L cells in response 
to the presence of nutrients in the lumen of the small intestine. GLP-1 has potent blood glucose-lowering 
action only during hyperglycemia, as it induces insulin secretion, stimulates insulin sensitivity, reduces 
glucagon secretion in a glucose-dependent manner, and improves β-cell function.21-24 The first glucagon-
like peptide-1 receptor agonist (GLP-1RA), exenatide, was approved in the United States in 2005 as an 
adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. There are 
now multiple GLP-1RAs available and are used extensively in clinical practice in this population. GLP-1RAs 
are well-tolerated, improve glycemic control with a low risk of hypoglycemia, improve indices of β-cell 
function, improve systolic blood pressure, and are associated with sustained weight loss.25-30 With obesity 
and diabetes frequently occurring in tandem, weight loss became a desired side effect of the drug. The 
FDA approved the GLP-1RA, liraglutide, in 2014 for chronic weight management in obese (body mass index 
(BMI) ≥30 kg/m2) or overweight (BMI ≥27 kg/m2) adults who have ≥1 weight-related comorbidity such as 
hypertension, diabetes, or dyslipidemia as an adjunct to diet and exercise. In the 56-week SCALE trial, 
non-diabetic obese or overweight subjects were randomized to placebo vs. liraglutide at 3 mg daily, a 
higher dose than the 1.2-1.8 mg used in diabetics.31 Liraglutide provided significantly greater weight loss 
of 8% vs. 2.6% in placebo (P<0.0001). No serious adverse events occurred; hypoglycemia events were rare, 
and none required professional intervention. The durability and excellent safety record of GLP-1RAs were 
also shown in a 5-year study of weekly exenatide subcutaneous injections; the weight reduction effect 
was sustained, and there were no major hypoglycemia or safety concerns. Importantly, the GLP-1RAs, 
semaglutide and liraglutide, have been shown to improve cardiovascular outcomes in type 2 diabetes.32-
34  

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Preliminary data: Lipohypertrophy in the era of contemporary ART is linked to higher HIV-1 RNA and 
not to ART class: We investigated the % change in abdominal SAT and VAT by CT scan in a 96-week study 
of 328 HIV-infected, ART-naïve participants who received tenofovir disoproxil fumarate-emtricitabine 
(TDF/FTC) and were randomized to receive either a PI (ritonavir-boosted atazanavir (ATV/r) or darunavir 
(DRV/r)) or the INSTI, raltegravir (RAL), as part of the AIDS Clinical Trials Group (ACTG) study, A5260s, a 
sub-study of A5257.36 At week 96, a 30% increase in VAT was seen in all arms regardless of regimen 
(Figure 1). Participants with a baseline HIV-RNA 
>100,000 copies/mL had double to triple the amount of 
VAT gain compared to those with lower HIV-RNA levels, 
despite no observed difference in VAT changes based 
on ART regimen. In an analysis of the large parent study 
A5257, we found that the odds of severe weight/BMI 
gains (≥10% gains from baseline) over 96 weeks of ART, 
were higher for subjects initiating RAL when compared 
to the PIs.8 These studies highlight the current 
unfortunate reality that no available HIV treatment is 
void of metabolic complications, and total and visceral 
fat accumulation occurs with all available ARTs.   
Enhanced inflammation in HIV: We investigated the effect of ART on systemic inflammation by evaluating 
changes in inflammatory markers with ART initiation in ACTG 5224s, the metabolic sub-study of A5202, in 
which 1857 HIV-infected, ART-naïve PLWH were randomized to receive either abacavir (ABC)/lamivudine 
(3TC) or TDF/FTC with either efavirenz (EFV) or ATV/r.37 By week 96, soluble tumor necrosis factor 
receptor (sTNFR)-I, sTNFR-II, soluble vascular cellular adhesion molecule-1 (sVCAM-1), and soluble 
intercellular adhesion molecule-1 (sICAM-1) decreased significantly within each arm but without 
significant differences between arms. However, overall, high-sensitivity C-reactive protein (hsCRP) did not 
decrease significantly, and, in fact, at 96 weeks, participants who received ABC/3TC/EFV had a significantly 
higher level of hsCRP than at baseline.  
Pre-ART and time-updated inflammation markers predict clinical events: In A5224s, we assessed the 
relationship between inflammation markers and incident clinical events.38 Pre-ART hsCRP, IL-6, sTNFR-I, 
and sTNFR-II were significantly associated with an increased risk of clinical events (even after adjustment 
for ART, CD4 count, and HIV RNA). Moreover, on-study changes in sTNFR-I and sTNFR-II were significantly 
associated with increased event risk, independently of ART, CD4 count, and HIV RNA. 
Inflammation markers are correlated with diabetes and CVD markers in HIV: We measured inflammation 
markers and carotid intima-media thickness (cIMT), a surrogate 
measure of subclinical atherosclerosis, in 94 PLWH and HIV-
uninfected, matched controls.39 cIMT, hsCRP, IL-6, and sVCAM-
1 were significantly higher in PLWH. Also, hsCRP, TNF-α, and 
sVCAM-1 were independently associated with cIMT. In another 
study,40 we found that at week 48 after ART initiation, PLWH in 
the highest quartile of sTNFR-I had increased odds of 
developing diabetes, compared to those in the lowest, even 
after adjustment for age, CD4, BMI, and PI use (Figure 2). Similar 
results were seen for sTNFR-II. Particularly pertinent to this 
current application, among measured inflammatory markers, 
only TNF-α receptors were predictive of incident diabetes, 

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supporting the hypothesis that chronic TNF-α exposure in HIV could lead to decreased GLP-1 secretion, 
which ultimately could cause abnormalities in glucose metabolism. 
Trunk fat correlates with monocyte activation and systemic inflammation: As part of a randomized, 
placebo-controlled trial of rosuvastatin in 147 PLWH on ART with mostly undetectable HIV RNA and with 
low-density lipoprotein (LDL) cholesterol <130 mg/dL, measurements were obtained at study entry for 
trunk and limb fat (as measured by dual-energy x-ray absorptiometry (DXA)), monocyte activation markers 
(sCD14 and sCD163), and markers of systemic inflammation. Overall, 50% of participants were on a PI-
containing regimen. Trunk fat correlated with insulin resistance (as measured by homeostatic model 
assessment of insulin resistance (HOMA-IR); r=0.58, P<0.0001), sCD14 (r=0.19, P=0.018), sCD163 (r=0.23, 
P=0.005), hsCRP (r=0.30, P<0.0001), IL-6 (r=0.20, P=0.017), and sTNFR-I (r=0.26, P=0.0015). The study 
supports the hypothesis that central fat accumulation in HIV is linked to monocyte activation and systemic 
inflammation.   
Importance of the trial:  
The pathogenesis of lipohypertrophy in HIV remains elusive. Obtaining visceral adipose tissue from PLWH 
has been a major hurdle and cannot be done electively as part of a human subjects research protocol 
(without another medical reason necessitating surgery). Past investigations have focused on the role of 
ART agents (in particular, PIs) on the central fat accumulation seen in successfully-treated HIV infection. 
Recently, it became apparent that fat accumulation is not specific to any class of antiretrovirals, and, thus, 
the focus has shifted to include the possible direct and indirect effects of the virus, which are known to 
cause a chronic inflammatory state. Yet, the pathogenesis remains elusive. Even more, it remains unclear 
whether the excess visceral fat accumulation in HIV is merely due to a “return to health” phenomenon 
with an accompanying improvement in appetite and normalization of the resting energy expenditure 
(REE) after successful ART. And, therefore, simply represents a manifestation of obesity in PLWH.  
For the first time in HIV, we will be able to carefully study the secretion of two gut hormones, GLP-1 and 
glucose-dependent insulinotropic polypeptide (GIP), stratified by HIV status. These metabolic hormones 
are released from the gut upon nutrient ingestion and are known for their insulin-stimulating effects, as 
well as their link to visceral fat accumulation and obesity. These have never been assessed 
comprehensively in PLWH in conjunction with measurements of visceral fat and glucose metabolism. In 
addition, since chronic inflammation (such as that seen in HIV) has been shown to alter the secretion of 
these hormones, we will also be able to study the relationship between these metabolic gut hormones, 
markers of inflammation and immune activation, and metabolic endpoints (VAT and insulin resistance). 
The data acquired from our proposed study will not only shed light on the pathogenesis of HIV-related 
lipohypertrophy but will also investigate a novel therapeutic intervention that could attenuate this 
concerning phenomenon and its associated co-morbidities.  
Regardless of the underlying causes, there is a pressing need for effective treatment of the body 
composition changes and cardiometabolic abnormalities associated with HIV infection. Evidence-based 
guidelines to manage these complications are lacking, as is the understanding of the consequences of 
reversing the excess fat (VAT and ectopic fat) on the downstream CVD risk. We and others have previously 
shown that several single-agent strategies (e.g. growth hormone-releasing factor, glitazones, metformin, 
and statins) have each proven to be of partial benefit on certain aspects of HIV-related cardiometabolic 
abnormalities. However, a single therapy is needed to comprehensively reverse the numerous 
abnormalities contributing to this increased cardiometabolic risk among PLWH. GLP-1RAs are appealing 
candidates for such a therapy because of their proven multifaceted effect in the obese (HIV-uninfected) 

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population, and, specifically, in light of the recent finding that a heightened inflammatory state (such as 
seen in HIV) impairs secretion of GLP-1.35 Thus, GLP-1RAs could be an excellent tool to fight the triple 
threat facing the success of long-term HIV management: 1) excess fat accumulation and ectopic fat 
deposition, 2) insulin resistance and high prevalence of diabetes, and 3) heightened inflammation, 
endothelial dysfunction, and CVD. The planned comprehensive studies will assess the efficacy and safety 
of GLP-1RA in PLWH, the mechanisms by which GLP-1RA improves the metabolic profile, and the 
downstream effects on CVD risk in HIV.  
There are multiple reasons why studying GLP1-RAs in the HIV population is of paramount importance. 
Despite a proven safety and efficacy record of GLP-1 RAs in HIV-uninfected populations, such data are 
lacking in the setting of HIV infection. PLWH represent an aging population with a high risk for metabolic 
and cardiovascular alterations. All PLWH are currently maintained on a combination of antiretroviral 
drugs, none of which have been proven to be benign on cardiometabolic indices. In addition, even 
virologically-controlled HIV infection is associated with a state of heightened inflammation and immune 
activation which may alter gut hormone secretion and, thus, the efficacy of the GLP1RAs. In addition, the 
proven beneficial CVD effect of GLP-1RA among diabetics led to the FDA approving the use of some of 
these drugs for CVD prevention in this population. HIV itself and/or antiretrovirals have been associated 
with endothelial dysfunction, arterial stiffness, and a high risk of CVD events. It is crucial to study the effect 
of GLP1-RAs in the setting of HIV infection, where heightened inflammation and metabolically-toxic 
antiretrovirals could significantly alter the efficacy of the intervention. In other words, we cannot 
extrapolate results from interventions (like GLP1-RAs) in HIV-uninfected populations and apply them to 
our patients with HIV who are very different. The addition of a parallel study, with similar intervention 
and evaluations, in an HIV-uninfected control group will add insight to the specificity of the intervention 
by HIV status. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
  
The potential risks for taking part in this study are: 
 
- 
Risk of loss of confidentiality: There is a risk of loss of confidentiality. We will make every effort to 
minimize this risk (section below and 10.1.3 outline the different measures taken to decrease this 
risk). 
 
- 
Blood tests: There is a minimal risk associated with obtaining blood, including discomfort, bruising, 
bleeding, fainting, and infection.  
 
- 
Risks of fasting: Some individuals find fasting or abstaining from smoking or caffeine to be 
bothersome. It may make some individuals feel anxious, irritable, or hungry. Participants who are 
required to take their morning medications with food should wait until after the visit has been 
completed to take their medications.  
 
- 
Risk of 4-hour MMTT: Some participants may feel a temporary sense of abdominal fullness and 
discomfort. Some may also have nausea, vomiting or diarrhea, but this is rare. Participants may also 
not like the taste of the Ensure Plus® shake, and it may leave an unpleasant taste in their mouth.   
 

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- 
Risks of radiation from abdominal CT scan (for visceral fat and liver fat assessments): We are 
exposed to radiation daily both from natural (sun and earth) and manmade sources. The average 
radiation dose from these sources for those living in the United States is 363 millirems per year. 
Exposure of up to 5,000 millirems of radiation is allowed in individuals who use radiation in their work 
(such as radiologic technologists and radiologists). Moreover, there is no evidence that a dose up to 
5,000 millirems per year is associated with any risk. By comparison, the radiation dose that 
participants will receive from a CT scan of the abdomen (liver and fat) in this study is approximately 
590 millirems (390 for the limited liver and 200 for single slice for fat). The scanning machines will not 
cause any physical discomfort other than from having to lie still on the table for the duration of the 
test.   
 
- 
Coronary CT scan for measurements of pericardial fat: A non-contrast, coronary CT scan will be 
utilized for measurements of pericardial fat. The dose of radiation used with this new technology is 
estimated to be 80 mrems, which is less than 1/10th of a diagnostic CT scan of the thorax.  
 
- 
Whole-body DXA scan: Measurements of whole-body DXA for assessments of fat and lean mass is 
negligible (~3 mrems of radiation).   
 
- 
PWV: This is a non-invasive test and does not carry any known risks.  
 
- 
Semaglutide intervention: The most commonly reported side effects noted with semaglutide are 
gastrointestinal-related, including nausea, vomiting, diarrhea, abdominal pain, and constipation, 
which tend to improve with time. Minor hypoglycemia (suggestive symptoms and glucose <55 mg/dL) 
occur in a very small number of people. Hypersensitivity reactions to semaglutide or any of its 
components can occur and, in studies, occurred at a rate of 1%. In all GLP-1RAs, injection site reactions 
(mostly pruritis, tenderness, nodule or redness) are possible, but tend to be mild and occur in similar 
frequency to placebo injections. Injection site reactions were only reported in 0.2% of semaglutide-
treated subjects in clinical trials. Renal dysfunction has also been described, usually in people with 
known pre-existing renal disease. Use of GLP-1RAs can also increase the risk of gallbladder and bile 
duct disease, and cholelithiasis has been reported with the use of semaglutide. Semaglutide was also 
associated with an increase in retinopathy complications in diabetics in a small percentage of 
participants over the course of a 2-year trial with diabetes (3% compared to 1.8% in placebo over a 2-
year trial. Rare cases of pancreatitis have been reported with the use of GLP-1RAs. Other adverse 
reactions that have been reported in small numbers include fatigue, dysgeusia, and dizziness. 
Semaglutide may also slow gastric emptying (gastroparesis) which could potentially impact absorption 
of concomitantly administered oral medications. In clinical trials, a mean increase in heart rate of 2-3 
beats/minute were reported with semaglutide. The FDA has added a warning in the package insert 
for all GLP-1RAs about a possible increased risk of thyroid cancers, specifically medullary thyroid 
carcinoma. Data in this regard come from research in rodents and happened in a dose- and duration-
dependent manner. It is unclear how this risk will translate in human use. There is no evidence of such 
tumors in semaglutide-treated subjects; however, such (rare) cases have been observed with the use 
of another GLP-1RA, liraglutide.  
 
- 
Cognivue is an FDA-cleared computerized testing tool rooted in adaptive psychophysics and designed 
to assess early signs of cognitive impairment. It received FDA-clearance in June of 2015 as a 
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Cognivue® consists of 3 sub-batteries of 10 separately scored sub-tests presented in a 
 10-minute automated sequence. The first sub-battery measures visual salience and adaptive measures 
adaptive motor control. These results do not count towards the final score. They are used only to adapt 
the remaining sub-tests to the response characteristics of the individual subject. This ensures that only 
cognition is evaluated, and the subject is not at a disadvantage because of visual or motor deficits. The 
subsequent 2 sub-batteries include perceptual processing (letter, word, shape, and motion 
discrimination), and memory processing (letter, word, shape, and motion memory).   After the test, a 
two-page report is provided: it includes an overall score, with a subsequent breakdown into six key 
cognitive domains aligned with current standards: visuospatial, executive function, naming/language, 
memory, delayed recall, and abstraction. The second page has information on 2 additional important 
parameters: Reaction Time and Speed Processing. There are no risks associated with this test. 
Subjects will be provided with the questionnaire on a device in a private room in the SIU and asked to 
complete the questions. This device uses a turn wheel for patients to answer the questions to their 
individual pace. A two-page report will be provided to the study team.  These results will not be shared 
with subject or provider as it is not a clinical test, and no clinical intervention will result. The lower the 
score the higher the risk of neurocognitive impairment is present however the goal is to identify the 
mild impairment which is has an unclear clinical significance.  Cognitive impairment can be a result from 
many underlying conditions including inflammation, metabolic conditions and lifestyle choices. It has 
been shown in HIV that co-morbidities have led to higher neurocognitive dysfunction and higher 
inflammation. We believe that modulating inflammation may be able to improve neurocognitive 
dysfunction. 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
Study participants may not benefit from the intervention. So far, the management of lipohypertrophy in 
HIV remains unclear, and this study will comprehensively assess a potential strategy that could improve 
both fat alterations, insulin resistance, and cardiovascular disease risk. 
In the HIV-uninfected population GLP-1RAs are well-tolerated, improve glycemic control with a low risk 
of hypoglycemia, improve indices of β-cell function, improve systolic blood pressure, and are associated 
with sustained weight loss.25-30 
The durability and excellent safety record of GLP-1RAs were also shown in a 5-year study of weekly 
exenatide subcutaneous injections; the weight reduction effect was sustained, and there were no major 
hypoglycemia or safety concerns. Importantly, semaglutide has been shown to improve cardiovascular 
outcomes in type 2 diabetes on the long term.32-34 
 This study is very important to the HIV population, as currently the pathogenesis of HIV-related 
lipohypertrophy is not understood. We think that the potential for benefit outweighs the risk of 
participating in this study because of the low potential for adverse events.  
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
There are multiple reasons why studying GLP-1RAs in the HIV population is of paramount importance. 
There is a pressing need for effective treatment of the body composition changes and cardiometabolic 
abnormalities associated with HIV infection. Evidence-based guidelines to manage these complications 
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on the downstream CVD risk. Despite a proven safety and efficacy record of GLP-1RAs in HIV-uninfected 
populations, such data are lacking in the setting of HIV infection, and results from HIV-uninfected 
individuals cannot simply be extrapolated to the HIV-infected population. 
HIV-infected individuals represent an aging population with a high risk for metabolic and cardiovascular 
alterations. The potential benefits of GLP1-RAs in HIV-infected individuals on fat accumulation, 
inflammation, immune activation and CVD prevention outweigh the risk of adverse events associated with 
this drug and the risk associated with this study protocol.  
To minimize the known potential risks as described in Section 2.3.1, the following measures will be 
employed to protect participants:  
- 
Confidentiality: We will make every effort to minimize this risk. Only IRB-approved research staff will 
have access to identifiable private information about the participants. Patient clinical and laboratory 
data will be collected on standardized forms which will be kept in locked filling cabinets in locked 
offices and/or stored on HIPAA-compliant, password-protected, cloud-based storage system “Box” 
and/or REDcap and only accessible to study staff. Each participant will be assigned a coded number, 
and this number will be used to identify the participant. All laboratory specimens, evaluation forms, 
reports, and other records will be identified by coded number only to maintain participant privacy. All 
computer entry and networking programs will be done with coded numbers only. Any material or 
data sent to non-study staff personnel will contain only de-identified information. No names or 
personal information will be used to identify the subjects. Clinical information will not be released to 
the participant’s private physician, clinic, or any other entity without permission of the subject, except 
as necessary for monitoring by the IRB, FDA, NIH, or as required by law. Release of information will 
be documented from subjects before requesting any medical records from outside clinics, and 
associated documents will only be sent/received from HIPAA-compliant, secured fax lines. Study staff 
will only talk to participants or participants’ representatives when phone calls are made for 
recruitment, retention, or adherence reasons, and any message left will have no mention of HIV. 
Recruitment material or any information given to participants (e.g., date reminders for study visits) 
will not mention HIV. Any publication of this study will not use the participant’s name or any personal 
identifiers. Both study sites will ensure that appropriate measures are taken to protect the privacy 
and confidentiality of all personally-identifiable health information (PHI) for which it is responsible. 
The proposed studies will include compliance with all regulations set forth by the HIPAA Privacy Rule, 
as well as with existing State and Federal laws pertaining to PHI.  
 
- 
Phlebotomy: Risks associated with blood draws will be minimized by proper blood drawing practices 
performed by a trained MD, RN, or phlebotomist. Universal precautions and sterile technique will be 
used. Participants will be monitored for adverse effects and counseled about the small risk of 
infection. In addition, the total amount of sample collection will be determined for each participant 
and reflect adaptations from several national guidelines, including the NIH Clinical Center. We will 
exclude any person with a hemoglobin <10 g/dL. 
 
- 
Fasting/MMTT: We will observe for signs/symptoms associated with hypoglycemia during all fasting 
study visits. Glucose levels will be monitored closely throughout the MMTT. Meals will be given to 
participants once fasting is no longer required for the study visit. If any participant has clinical 
signs/symptoms associated with fasting, the study visit will be stopped, and the participant will be 
given juice/food or any other intervention, as necessary.  
 

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- 
Radiation exposure: Pregnant/lactating women will be excluded from study participation. A urine 
pregnancy test will be performed prior to obtaining any imaging studies that are associated with 
radiation exposure. If a person is deemed to be at an increased risk of any kind due to the minimal 
radiation associated with these tests, he/she will not be enrolled in the study or will be terminated 
from study participation.  
 
- 
Side effects of study drug: Our exclusion criteria protect certain vulnerable people from potential side 
effects associated with GLP-1RAs. We will exclude anyone with diabetes or renal dysfunction, a history 
of alcohol abuse, pancreatitis, thyroid cancer, or a family/personal history of medullary thyroid 
carcinoma or MEN type 2. We will also exclude anyone with excessive alcohol intake, an elevated 
lipase or liver enzymes, and active gastrointestinal symptoms, as described in the inclusion/exclusion 
criteria. Pregnancy and lactation are exclusionary. Once enrolled in the study, participants will be 
monitored very closely for any side effects of the study drug and adverse events. Participants will 
undergo an 8-week titration period prior to receiving the full 1 mg dose. This titration period will 
consist of 4 weeks of 0.25 mg dose followed by 4 weeks of 0.5 mg dose. Their blood will be measured 
for serial safety laboratory tests, including comprehensive metabolic panels, which will include 
creatinine, lipase, among others. We will also monitor for clinical signs and symptoms suggestive of 
any concerning conditions, such as pancreatitis, thyroid dysfunction, etc. We will educate participants 
of important signs/symptoms, and they will be instructed to contact a member of the study team (24 
hours/day by pager) with any concerns. In terms of the theoretical increased risk of thyroid cancers, 
the FDA did not find it useful to routinely monitor thyroid tests, thyroid ultrasound, or calcitonin 
levels, as these may lead to unnecessary evaluations. Participants with any of sign/symptoms 
concerning for this diagnosis will have his/her study drug withheld until the diagnosis is ruled out. 
Otherwise, participants will be permanently taken off study drug. Our interventional portion of the 
study is short (32 weeks only), and we will use an FDA-approved dose of semaglutide. 
 
- 
Adverse events: All adverse events will be recorded in case report forms and graded per NIH 
guidelines. All >Grade 1 adverse events deemed possibly-, probably- or definitely-related to study 
participation will be reported to the local IRBs yearly and to the DSMB at the next meeting and will be 
presented in scientific publications. All >Grade 2 adverse events deemed to be possibly-, probably- or 
definitely-related to study participation will be reported to both institutions, the data safety and 
monitoring board (DSMB), NIH, and FDA within one week in writing. Any adverse event that requires 
medical attention will be addressed locally by the PI, and the participant will be referred to their PCP 
or emergency department, if deemed medically necessary. 
 
- 
Incidental findings: Any incidental finding deemed clinically-relevant will be discussed with the 
participant, so that the participant can obtain medical treatment from his/her PCP or local emergency 
department. With permission from the participant, any relevant information will be sent to his/her 
PCP or emergency department, and the PI will contact the provider directly.  
 
- 
Additional protection against risks: Participation of human participants in research is under the 
jurisdiction of federal regulations (45 CFR 46 and 21 CFR 50 and 56). Investigators at both sites are 
granted the privilege of working with human participants under normal assurance to the government 
that such research complies with regulations protecting human participants. Both universities have a 
federal-wide assurance for research with human participants and are in compliance with federal 
policy governing use of human participants. All human participant protocols are reviewed through the 
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Association for Accreditation of Human Research Protection Programs (AAHRPP). All people involved 
have completed the University of Miami computer-based CITI Human Participants Research Education 
Course, which requires periodic re-certification. All research activity, informed consents and 
continuing reviews will be reviewed by the appropriate IRBs, in compliance with 45CFR46 before the 
research is started and continuing review will occur annually. The research staff will ensure that all 
information needed for continuing review is at the IRB in accordance with IRB requirements. After the 
study is completed, all data will be kept according to NIH and FDA regulations. All the procedures will 
be performed by the PI, trained study coordinators or study nurse. A data safety and monitoring board 
(DSMB) has been created to review interim data and oversee adverse events. 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
Primary 
 
 
To assess the effects of 
semaglutide on visceral 
and ectopic fat in HIV-
infected participants with 
lipohypertrophy after 32 
weeks of treatment 
-Visceral and subcutaneous 
adipose tissue (by abdominal 
CT scan) 
 
-Total, limb, trunk fat (by DXA 
scans) 
 
-Pericardial fat (measured by 
non-contrast chest CT)  
 
 
 
 
-DXA scans were previously used to 
assess longitudinal changes in fat after 
ART initiation or after interventions for 
lipodystrophy.4,36,123,124 We will use the 
same standardized protocol on all study 
participants and each participant will 
have longitudinal measurements 
obtained on the same machine. DXA 
scans from both sites will be read at 
Case by a single radiologist, blinded to 
study arms and study information. 
 
-The effect of GLP-1RA treatment on 
pericardial fat in HIV is unknown, as are 
the relationships between changes in 
pericardial fat and changes in insulin 
resistance and VAT. Thus, pericardial fat 
measurements will yield novel and 
informative data. 
 Secondary  
 
 
To examine the effects of 
semaglutide on lean body 
mass, inflammation, 
immune activation, 
cardiovascular disease 
risk, gut integrity, and gut 
hormones in HIV-
infected individuals with 
lipohypertrophy after 32 
weeks of treatment. 
 
 
 
-Markers of monocyte 
activation: sCD14 and sCD163  
 
-Markers of systemic 
inflammation: hsCRP, IL-6, 
sTNFR-1, sTNRF-II  
 
-Gut integrity and microbial 
translocation will be assessed 
by I-FABP, zonulin-1, LPS 
 
-The selected markers of monocyte 
activation and systemic inflammation 
have been previously shown to be 
associated with co-morbidities in 
HIV38,39,136 and are relevant to adipose 
tissue, insulin resistance, and CVD. 
 
-Pulse wave velocity is a non-invasive 
measure of arterial stiffness, and was 
shown to be associated with CVD 
events.97 
 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
-Markers of endothelial 
function: pulse wave velocity 
and EndoPat 
 
 
 
 
 
 
 
 
-EndoPat, is non-invasive, reproducible, 
and strongly correlates with coronary 
endothelial function (r=0.79; P<0.001).14 
Endothelial dysfunction predicts 
atherosclerosis,99,100  
Tertiary/Exploratory  
 
 
To elucidate potential 
mechanisms by which 
semaglutide affects 
visceral and ectopic fat. 
 
-Adipokines measures (leptin, 
adiponectin, resistin, and 
visfatin) 
 
-Natriuretic peptides (BNP 
and ANP) 
-Adipokines and natriuretic peptides will 
be measured to help elucidate the 
potential mechanism by which GLP-1 
may affect metabolic endpoints. 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
The main objective of this study is to assess the potential beneficial effect of GLP1-RA on visceral and 
ectopic fat accumulation, insulin resistance, inflammatory markers and the downstream effect on 
cardiovascular disease risk assessment in HIV-infected individuals.  
 
This study is a phase IIb, randomized, double-blinded, placebo-controlled clinical trial of the GLP1RA, 
semaglutide. The duration of the study will be 56 weeks. Patients will be recruited from 1 site (Cleveland, 
OH).  
 
A population of HIV-infected individuals with lipohypertrophy will be studied. The interventional phase 
will last 32 weeks, followed by a 24-week observational phase to assess the sustainability of the 
intervention. 
 
Patients will be randomized equally to one of 2 treatment arms: 
1) Semaglutide 1.0 mg, given by weekly subcutaneous (SC) injection, after the initial 8-week titration. 
2) Matching placebo given by weekly SC injection  
 
Randomization will be performed at week 0. Those randomized to active semaglutide will be given 0.25 
mg SC weekly for 4 weeks then 0.5 mg SC weekly for 4 weeks then start the 1 mg SC weekly until week 
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Study drugs will be provided free of charge for study participants. Antiretroviral therapy will not be 
provided by the study. The decision for antiretroviral therapy changes or discontinuation will be left to 
the primary HIV provider, but these changes will be documented in the study chart and will be accounted 
for during the analyses.  
 
4.2 
JUSTIFICATION FOR DOSE 
 
We have selected once-weekly semaglutide 1.0 mg for this current study, as its properties and 
pharmacological profile make it, arguably, the most suited GLP-1RA to treat lipohypertrophy and 
cardiometabolic abnormalities in HIV..47-49 
 
We chose a weekly SC route of administration instead of a daily regimen, which is likely to increase 
adherence and retention in HIV-infected individuals who are not accustomed to regularly receiving 
injections; it is the ideal agent to use in this current study.  
 
A dose of 1 mg is the FDA-approved dose, and this dose showed superiority in reduction of body weight 
and glycemic control when compared to 0.5 mg dosage in SUSTAIN 1-6 trials.  However, to adhere to the 
package insert and the need to improve tolerability and decrease the potential for nausea and vomiting, 
we will titrate the drug over an 8-week period.  
 
4.3 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all study visits, 
including the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA), Section 
1.3. 
 
The end of the study is defined as completion of the last visit or procedure shown in the SoA in the trial 
globally. 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
To be eligible to participate in this study, participants must meet all of the following criteria: 
 
1. Male or female, aged ≥18 years. 
 
2. HIV-1 infection as documented by any licensed ELISA test kit and confirmed by Western blot at 
any time prior to study entry. HIV-1 culture, HIV-1 antigen, plasma HIV-1 RNA, or a second 
antibody test by a method other than ELISA is acceptable as an alternative confirmatory test. 
 
3. Body mass index ≥25 kg/m2. 
 
4. Waist circumference and waist-to-hip ratio >95 cm and >0.94 cm, respectively, for men, and >94 
cm and >0.88 cm, respectively, for women occurring in the context of HIV treatment. 

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5. Subjective evidence of increased abdominal girth occurring after initiation of HIV treatment. 
 
6. HIV-1 RNA <400 copies/mL for ≥6 months. 
 
7. Receiving a stable antiretroviral regimen for at least the last 12 weeks prior to study entry with 
cumulative duration of 1 year of treatment at the time of study entry. 
 
8. Provision of signed and dated informed consent form and is capable of reading and 
comprehending the informed consent. 
 
9. Stated willingness to comply with all study procedures and availability for the duration of the 
study.  
 
10. All women of child-bearing potential (WOCBP) must have a negative serum or urine pregnancy 
test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to start of 
study medication. WOCBP is defined as any female who has experienced menarche and who has 
not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy), who is not postmenopausal (defined as amenorrhea 12 consecutive months), or 
is on hormone replacement therapy (HRT) with documented plasma follicle-stimulating 
hormone level 35 mIU/mL. Women who are using oral, implanted, or injectable contraceptive 
hormones or mechanical products such as an intrauterine device or barrier methods 
(diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where 
partner is sterile (e.g., vasectomy), should be considered of child-bearing potential. 
 
11. Female subjects who are not of reproductive potential (have reached menopause or undergone 
hysterectomy, bilateral oophorectomy or tubal ligation) or whose male partner has undergone 
successful vasectomy with resulting azoospermia or has azoospermia for any other reason, are 
eligible without requiring the use of contraception. Patient-reported history of menopause, 
sterilization, and azoospermia is considered acceptable documentation. 
 
12. All subjects must not participate in a conception process (e.g. active attempt to become 
pregnant or to impregnate, sperm donation, in vitro fertilization), and if participating in sexual 
activity that could lead to pregnancy, the female subject/male partner must use condoms (male 
or female) in addition to one of the following forms of contraception while on study: either a 
spermicidal agent, diaphragm, cervical cap, IUD, or hormonal-based contraception. 
 
13. Have no plans to alter antiretroviral therapy, or to undergo any weight loss program, formal 
exercise training or surgery during the study period, or initiate structured/strategic antiretroviral 
treatment interruptions.  
 
 
5.2 
EXCLUSION CRITERIA 
 
Main exclusion criteria: 
 

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1. Known cardiovascular disease or diagnosed diabetes. If on metformin without a diabetes 
diagnoses metformin use has to be constant, uninterrupted for 6 months prior to entry.  
 
2. Any active or chronic uncontrolled inflammatory condition, infection or cancer.  
 
3. Women who are pregnant or breastfeeding.  
 
4. Women with a positive pregnancy test on enrollment or prior to study drug administration.  
 
5. A clinically-relevant illness within 14 days prior to study entry not explicitly excluded by the 
protocol, a physical or psychiatric disability, or a laboratory abnormality that might place the 
subject at increased risk by being exposed to the medications in this study or which might 
confound the interpretation of this investigation.  
 
6. Active gastrointestinal symptom Grade >1 within the last month.   
 
7. Regular use of immunomodulators/agents which could impact inflammation. Regular use of 
NSAIDS allowed if constant, uninterrupted for 6 months and no plans to alter. Statin use must also 
be constant, uninterrupted for 6 months prior to study entry. Thyroid medication allowed unless 
diagnosed with uncontrolled thyroid disease. 
 
8. Inability to communicate effectively with study personnel. 
 
9. Use of megestrol acetate, testosterone, or any steroid use beyond normal amounts found in the 
body within 6 months of study, or intend to start. 
 
10. Glomerular filtration rate <50 cc/min/1.73 m2. 
  
11. Hemoglobin <10 g/dL. 
 
12. Elevated lipase level >1.5 upper limit of normal 
 
13. AST AND ALT >2.5x upper limit of normal. 
 
14. Use of growth hormone or growth hormone-releasing hormone in the last year, or intent to start. 
 
15. History of excessive alcohol use (on average 2 or more drinks a day), pancreatitis, thyroid cancer, 
or a diagnosis of multiple endocrine neoplasia (MEN) syndrome type 2. 
 
16. Weight 450 lbs. or higher 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
Individuals should have no plans to undergo any weight-loss program, formal exercise training or bariatric 
surgery during the study period. HIV-infected participants should additionally have no intention to initiate 
structured/strategic antiretroviral treatment interruptions. 
 

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For specific study visits (for the entry visit and week 32 of the interventional phase, and for week 56 of 
the observational phase), participants will be asked to be fasting for ≥12 hours prior to the study visit (as 
defined by no food or drink, except for plain water and medications). Participants will also be asked to be 
free of tobacco and caffeine for these visits, for at least 4 hours before PWV measurements. 
 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants, to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any serious adverse event (SAE). 
 
Patients who do not meet the criteria for participation in the trial due to modifiable factors (examples: 
active gastrointestinal symptoms >Grade 1 within the month prior to enrollment, pregnancy, lactation) 
might be rescreened with resolution of the specific factor/condition.   
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Recruitment:  
Participants will be enrolled at the Cleveland site. Sources of study participants include: 1) the 1,180 
established patients currently followed in the HIV clinic at Case Western Reserve University (25% women, 
40% African American, 3% Hispanic); 2) patients seen at the HIV Metabolic Center, led by Dr. McComsey, 
a referral center established in 2004 that serves the entire northeastern portion of Ohio for evaluation 
and treatment of HIV-related metabolic complications. People are referred by their HIV providers or are 
self-referred for HIV-related metabolic concerns or for interest in participating in our metabolic clinical 
trials. The most common reason for referral has been, and continues to be, lipodystrophy. Each person 
undergoes a full metabolic assessment, including anthropometrics. The majority have failed attempts at 
diet and exercise, and among the last 82 patients seen for lipohypertrophy, only one has ever been treated 
with tesamorelin; 3) Dr. Corrilynn Hileman, the Clinical Director of the HIV clinic at MetroHealth Medical 
Center (a Case affiliate and located within short distance geographically to Case) and close collaborator 
with both PIs, will identity and refer potential participants to Case. MetroHealth currently provides HIV 
care to 1615 adults (23% females, 52% African American, and 13% Hispanic).  
Recruitment will be conducted like prior studies conducted by the PIs and will be maximized through a 
combination of education and outreach. Clinic recruitment methods will include: 1) IRB-approved 
recruitment flyer in the clinics; 2) study staff will approach patients during their routine medical visits after 
approval of their health care provider; and 3) case manager/physician referrals.  
Inclusion of Women: The enrollment of females with HIV in cardiometabolic studies is of great 
importance. There is a remarkable paucity of data regarding females living with HIV and ART-associated 
cardiovascular and metabolic complications. In addition, female gender has been identified as a risk factor 
for some metabolic toxicities, including lipodystrophy. 
At the Case Western Reserve University site, the AIDS Clinical Trials Unit (ACTU), part of the NIH-funded 
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Specifically, in Dr. McComsey’s trials through the Case HIV Metabolic Center during the past 7 years, she 
has enrolled a proportion of women of 40%, which is higher than the proportion of female patients in 
their clinic (~20%). In prior non-ACTG metabolic studies conducted by Dr. McComsey at Case that required 
invasive tissue biopsies, 29% (60/206) of enrolled participants were females. 
Dr. McComsey’s prior success in enrolling female participants was due, in part, to constant outreach 
activities performed by Dr. McComsey with regular conferences and educational sessions in women focus 
groups. Enhancement of women’s knowledge about metabolic co-morbidities associated with HIV helped 
her tremendously with enrollment in prior trials. Indeed, the study team will continue these efforts to 
improve women’s knowledge about HIV, and, in particular, about metabolic and cardiovascular 
complications associated with HIV and HIV treatment. 
Inclusion of Minorities: Case has been successful in enrolling minorities in clinical trials due to extensive 
outreach efforts geared toward local physicians in general and those treating people with HIV, AIDS 
service organizations, people live with HIV and those at risk for HIV, and the general public. During the 
past 6 years, the ACTU has enrolled in their trials a proportion of racial and ethnic minorities proportional 
to the population seen in their clinic and in Cuyahoga County (40% and 3%, respectively), where the clinic 
is located. Dr. McComsey’s studies have had enormous success in enrolling racial minorities. For example, 
in a previous clinical trial of rosuvastatin in people with HIV, 101/147 (70%) of study participants were 
African American. Recruiting people from MetroHealth Medical Center, a Case affiliate, where the HIV 
clinic is comprised of 52% African Americans and 13% Hispanics will further enhance enrollment of 
minorities at the Case site.  
Studying the effects of GLP-1RAs among African Americans is of high importance, as they are at an 
increased risk of obesity, diabetes, and cardiovascular disease compared to the general population. 
Therefore, MUSC has been added as a study site to increase enrollment of African-American participants. 
Her clinic is comprised of 73% African American patients with HIV, a proportion that is mirrored among 
the local clinics that have agreed to help refer eligible patients.   
Inclusion of Children: Only adults 18 years of age and older will be enrolled in the proposed study, as 
there are limited data on the safety of GLP-1 receptor agonists in children. In addition, given the 
inclusion/exclusion criteria outlined in this proposal, few children would qualify for the study.   
Illiterate Subjects: Subjects with all levels of literacy will be eligible for this study.  The consent document 
will be read to those volunteers with less than an 8th grade equivalent level of literacy.  Subsequently, the 
informed consent will be signed by the volunteer making their mark in the signature section in order to 
document their understanding.  A witness will be present to confirm the consent process has taken place.  
Both the witness and person conducting the consent process will sign and date the consent.  The 
investigator obtaining consent will ask each subject to reiterate what will be required from them, risks 
and benefits, and their rights as a participant in order to ensure their full understanding of the study.  
Non-English-Speaking Subjects: Subjects who do not understand or speak English will also be eligible for 
this study. The consent form will be read to those non-English speaking study candidates in their primary 
language by a translator. A witness (who speaks English and the study subject’s language) will be present 
to confirm the consent process has taken place. Both the witness and person conducting the consent 
process will sign and date the consent. The investigator obtaining consent will ask the study candidate via 
the translator to reiterate what will be required from him/her, risks and benefits, and his/her rights as a 
participant to ensure their full understanding of the study. 

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Employees: Anyone with an employment or academic relationship to the Principal Investigator will be 
informed that their participation in a study, or refusal to do so, will in no way influence their employment, 
or subsequent recommendations. Employees will never be made to feel that their job, promotion, salary, 
or status in any way depends on participation in research studies. 
Retention:  
The PIs and study staff will utilize and expand upon previously successful efforts for study retention and 
adherence strategies including: (1) excluding people who anticipate transportation or feasibility issues 
during the study period; (2) financial compensation for time and travel ($25 for the following study visits: 
screening, week 9, week 14, week 20, week 26 and week 31; $50 for the following study visits: -1, Week 
0 and week 32; $75 for week 56. 3) paid parking for study visits; 4) food/drink during fasting study visits; 
5) reminder phone calls the day prior to scheduled appointments and additional calls to reschedule those 
who miss appointments; 6) additional use of participant’s preferred mode of communication including 
text messages and email for research visit scheduling, reminders, and rescheduling for missed 
appointments. A careful selection of study participants based on an established track record of kept clinic 
appointments, viral suppression, and stable ART will further improve study retention and adherence. In 
several prior 48-96-week trials requiring extensive metabolic assessments (e.g. tissue biopsies), our 
retention was >90%; thus, we do not anticipate any issues with study retention.  
 
6 
STUDY INTERVENTION 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
According to the drug package and FDA report (Semaglutide s.c. OW NDA 209637): 
Semaglutide is a selective GLP-1 receptor agonist (GLP-1 RA) with a long plasma half-life suitable for once-
weekly dosing. The long half-life was obtained by applying the fatty acid acylation technology that 
provides specific high-affinity albumin binding. Furthermore, semaglutide has full stability against DPP-4 
degradation. The inherent long half-life together with a low molecular weight of semaglutide is believed 
to ensure optimal efficacy. Semaglutide exhibits GLP-1 receptor-mediated effects, leading to lowering of 
glucose and decreased appetite through physiologically relevant mechanisms. As a result, semaglutide 
provides strong glycemic control and weight loss. In addition, the cardiovascular safety of semaglutide has 
been confirmed. The mechanism of action of semaglutide was characterized in extensive nonclinical and 
clinical studies. 
 
Ozempic® (semaglutide) injection 1 mg is indicated as an adjunct to diet and exercise to improve glycemic 
control in adults with type 2 diabetes mellitus and received FDA approval in December 2017:  
• 
Ozempic® is not recommended as a first-line therapy for patients who have inadequate glycemic 
control on diet and exercise because of the uncertain relevance of rodent C-cell tumor findings to 
humans. 
• 
Ozempic® has not been studied in patients with a history of pancreatitis. Consider other 
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• 
Ozempic® is not a substitute for insulin. Ozempic® is not indicated for use in patients with type 1 
diabetes mellitus or for the treatment of patients with diabetic ketoacidosis. 
• 
It is not known if OZEMPIC® is safe and effective for use in children under 18 years of age. 
6.1.2 DOSING AND ADMINISTRATION 
 
After an initial 8-week period of titration, semaglutide 1.0 mg will be administered by SC injection 
into the abdomen, thigh, or upper arm at any time of day on the same day each week, with or 
without food. If changing the day of administration is necessary, allow at least 48 hours between 
two doses. 
Rotate injection sites weekly if injecting in the same area of the body. Injection will not be mixed 
with other products (administer as separate injections).  
Patient will be instructed to avoid adjacent injections if administering other agents in the same 
area of the body.  
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
The study agent, semaglutide, is an FDA-approved drug indicated as an adjunct to diet and exercise to 
improve glycemic control in adults with type 2 diabetes mellitus. It is readily available from 
commercial/outpatient pharmacies and pharmacies affiliated with hospitals and tertiary-care academic 
centers. The investigational pharmacies (specialized pharmacies specifically designed for clinical trials) at 
the respective enrollment sites will oversee the acquisition, drug accountability, and dispensing of the 
study agent in accordance with local and federal regulations. The co-PIs (both MDs) and the study team’s 
RNs at the respective sites will administer the medication to the study participants. Because semaglutide 
has not been studied in people with HV-associated lipohypertrophy, the study team will apply for an IND 
from the FDA for this study protocol to help ensure participant safety.  
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
According to the Ozempic® label: 
NDC: 00169413602 
Generic name: Semaglutide 
Labeler: NOVO NORVODISK 
Brand name: Ozempic 
Color List: colorless 
Clarity: clear 
Strength Field Collection: 1 mg per dose (2 mg/1.5 mL) 
Dosage Form: Solution Pen-injector 
Discontinued: no 
Route List: subcutaneous 

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Contains List: phenol; propylene glycol 
Bioequivalency Rating: NR 
Rx/OTC: Rx (single source) 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
The investigational pharmacies at the respective sites will refrigerate the interventional drug according 
to the manufacturer’s recommendations at 36°F to 46°F (2°C to 8°C) until dispensed.  
 
6.2.4 PREPARATION 
 
Investigational pharmacies will dispense study drug or matching placebo (saline) in a pre-filled syringe 
which will be administered by study staff.  
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Participants will be randomized 1:1 to receive semaglutide by SC injection once weekly, or matching 
placebo, for 32 weeks. The initial 8 weeks will be the titration phase (0.25 mg SC weekly for 4 weeks then 
0.5 mg SC weekly for 4 weeks, then 1 mg SC weekly until week 32). The study statistician will generate 
randomization sheets which will be sent directly to the investigational pharmacists. After being provided 
to the pharmacists, the randomization schedule will be maintained in a locked, secured location at the 
pharmacy. Only site pharmacists can access the randomization schedule at the time of the intervention 
assignment. On the day of the visit, investigational pharmacies will dispense study drug or matching 
placebo (saline) in identical-appearing, pre-filled syringes that do not contain any indication of study arm.  
Al participants, study staff, key personnel, consultants and DMSB members will be blinded to treatment 
allocation. All participants will receive identical information regarding potential side effects adverse 
events. Unblinding of treatment allocation will occur only if warranted to optimize management of an 
adverse event or for other safety reasons. In these specific circumstances, the investigational pharmacist 
will be responsible for breaking the blind to the principal investigator. This will occur in a private location 
to ensure the rest of the team remains blinded.  
All statistical analyses will also be done in a blinded fashion. Data will be exported to the statistician as 
arm A versus arm B by the pharmacist to preserve blinding.  
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
Study drug (active or placebo) will be injected SC by the research staff once weekly, which will help ensure 
adherence and improve retention, as study participants will not have to worry about self-injecting.  
 
6.5 
CONCOMITANT THERAPY 
 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications that will be reported are prescription and over-the-
counter medications and supplements.  
 

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Data regarding concomitant medications will be collected at the screening visit. Additionally, at all study 
visits, patients will be asked to report any changes to their medication list.  
 
 
6.5.1 RESCUE MEDICINE 
 
Not applicable. 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
For any study participant who develops a ≥Grade 3 toxicity felt to be possibly- or probably-related to study 
drug, the study drug will be interrupted, and the participant promptly evaluated. If the ≥Grade 3 toxicity 
is deemed not to be related to the study drug, then the drug can be restarted (after symptoms resolve) 
with very close monitoring of recurrent symptoms. If a participant develops possible pancreatitis or 
thyroid cancer symptoms during the study, he/she will be promptly evaluated, and study drug withheld. 
If the diagnosis of pancreatitis or thyroid cancer is proven or likely, study drug will be permanently 
discontinued and the participant will be followed on-study, off-study drug. The investigators will also 
adhere to any recommendations made by the DSMB. In addition, if during the study, a participant 
develops diabetes requiring hypoglycemic agents, the study drug will be withheld, and the participant will 
be followed off study drug. At any point, if deemed medically-necessary, the participant’s study arm 
(placebo and active drug) will be unblinded, and the participant will be followed off study drug.   
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
CRITERIA FOR PERMANENT STUDY DISCONTINUATION: 
 
- 
Request by the participant to withdraw.  
- 
At the discretion of the FDA, IRB, DSMB, or NIH.  
- 
Pregnancy or breastfeeding. 
- 
Participant judged by the investigator to be at significant risk of failing to comply with the provisions 
of the protocol. 
- 
Request of the primary care physician if he/she thinks the study is no longer in the best interest of 
the participant. 
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for scheduled visits and is 
unable to be contacted by the research staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
 

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1. The research staff will attempt to contact the participant and reschedule the missed visit for 
another day during the same week and counsel the participant on the importance of 
maintaining the assigned visit schedule and ascertain if the participant wishes to and/or should 
continue in the study. 
2. Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls). Contact (and 
attempts to contact) will be documented in the participant’s medical record or study file.  
3. Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
a. Staff will ask the participant to return to clinic for a premature study discontinuation 
visit where week 56 evaluations will be followed.  
b.  
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
 
Screening and entry: 
Potential participants will be asked to visit the clinic at least once to be screened and ensure that they 
meet the requirements for entry into the study.  All screening evaluations to determine eligibility must be 
completed within 30 days prior to study entry. If a potential participant shows up ill with any acute 
symptom, the visit will be postponed until all symptoms have resolved for at least 7 days. Screening may 
take place on the same day as a normally-scheduled clinic appointment, if the person has been fasting for 
at least 12 hours. Before any tests or information can be obtained as part of this study, potential 
participants must undergo the informed consent process including providing written informed consent. 
The site PI or member of the study team will conduct the informed consent process and complete a 
checklist indicating date and time the consent was signed, who was present, version date, and if a copy 
was provided to participant that will be filed in the participant’s chart.    
 
As part of the screening process, participants will undergo: 
- 
A series of health-related questions to determine their eligibility.  
- 
A review of any applicable medical records and laboratory results as related to the 
inclusion/exclusion criteria. 
- 
A targeted physical examination, including height, weight, blood pressure, and anthropometric 
measurements. 
- 
A blood draw for hematology/chemistries as outlined in the inclusion/exclusion criteria. 
- 
An HIV test (when applicable). 
- 
For woman of reproductive potential, a urine sample will be taken for a pregnancy test.  
 
If a participant does not meet inclusion criteria, the reason for ineligibility will be noted in the 
participant’s study chart.  
Lead-in phase: After passing screening, eligible participants will enter the 4-week lead-in phase, and they 
will receive standardized dietary and physical activity advice from the clinic dietician. It is very unlikely 
that the dietary advice will generate any significant change in lifestyle habits as patients already receive 
this advice as part of standard of care. The 4-week run-in phase (with weekly visits) will help assess the 
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the most committed participants with the highest likelihood to adhere to study requirements and weekly 
visits. 
During the weekly visits, participants will undergo: 
- 
A targeted physical examination, including weight, blood pressure, and anthropometric 
measurements. 
- 
Detailed dietary and physical activity questionnaire. 
- 
At visit -1, participants will also undergo a test to measure gut hormone levels (4-hour mixed meal 
tolerance test). For this visit, subjects will be compensated $25.00. 
 
Interventional phase: The study statistician will generate randomization sheets which will be sent directly 
to the investigational pharmacists, and the respective sites’ investigational pharmacy will oversee 
randomization and dispensing of study drugs. On the first study visit of the investigational phase, the 
investigational pharmacy will dispense study drugs or matching placebo (saline) in a pre-filled, blinded 
syringe. Study drug (active or placebo) will then be injected subcutaneously by the research staff once 
weekly, in the abdomen, thigh or upper arm, at the discretion of the study participants in concurrence 
with the staff and independent of meals. Participants will be seen once weekly for injections and close 
monitoring. 
The interventional phase will consist of two phases: titration phase and full-dose phase. 
Titration phase: Participants will receive at W1, W2, W3, and W4 0.25 mg of semaglutide and then will be 
increased to 0.5 mg semaglutide at W5, W6, W7 and W8. This titration phase allows potential side effects 
to be monitored and participants to gradually increase to the 1.0 mg dose. Participants will receive a bus 
pass or parking voucher for this visit.   
After the 8-week titration phase, participants will start the 24-week full dose phase where semaglutide 
will be administered weekly at 1 mg SC dosing.  
At entry (week 0), week 14, 20, 26 and 32 study visits, participants will undergo a comprehensive clinical 
assessment with performance of safety laboratories (chemistries with lipase, hematology, and pregnancy 
test for women). HIV-1 RNA and CD4/CD8 will also be measured as part of routine care every 12 weeks. 
Fasting (≥12 hours) will be required for entry and weeks 20 and 32. A period of at least 4 hours of smoking 
and tobacco abstinence will be also required before study visits at entry and 32 weeks. 
Observational phase: After the 32-week interventional phase, participants will continue on to the post-
treatment observational phase, off study drug, and they will be seen at week 56 for the last study 
evaluation, as outlined in the table of study procedures. This visit will assess the durability of the 
intervention, and it will assess body composition, inflammation markers and cardiovascular outcomes. 
This visit will also be performed in a fasting state (≥12 hours) and will require a period of at least 4 hours 
of smoking and tobacco abstinence.   
Sources of materials: Sources of materials obtained from the participants will include self-reported data 
from questionnaires and interviews with study staff, medical records, physical examination/body 
measurements, non-invasive/non-radiative cardiovascular assessments, DXA scan, blood, urine, and 
stool.  

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DETAILED STUDY ASSESSMENTS AND PROCEDURES (timing of different procedures presented in Section 
1.3.1) 
- 
Detailed dietary assessments will be obtained by study staff, overseen by a registered dietician, and 
analyzed using the Nutrition Data System for Research (NDS-R) software version 2005.  
 
- 
Body image questionnaires will assess changes in the amount of fat at specific body sites, adopted 
from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM).121  
 
- 
Physical activity status will be assessed based on standardized questionnaires.122  
 
- 
Anthropometric measurements including weight, height, waist and hip circumferences will be 
obtained using standardized techniques.  
 
- 
Whole-body DXA scans will be used to assess changes in body composition, including measurements 
of total, limb, and trunk fat, and lean mass. We have used DXA to assess longitudinal changes in fat 
after ART initiation or after interventions for lipodystrophy.4,36,123,124 We will use the same 
standardized protocol on all study participants and each participant will have longitudinal 
measurements obtained on the same machine. DXA scans from both sites will be read at Case by a 
single radiologist, the co-I, Dr. AnsariGilani, blinded to study arms and study information.  
 
Abdominal CT (for body composition and liver fat) will be used to assess TAT, VAT, and SAT, as previously 
described.7  
-      Non-contrast CT of the abdomen will be obtained (Helical CT 3mm slice thickness with 3mm scan 
increment extending from the dome of the diaphragm through the symphysis pubis). Liver and spleen 
attenuation will be measured by averaging three circular regions of interest with an area of at least 2 
cm2 within the parenchyma of each organ on different axial slices, taking care to avoid vessels and 
bile ducts. The ratio of liver to spleen attenuation will then be calculated. In healthy individuals, the 
mean CT radiodensity for the liver is consistently higher than that for the spleen. As the fatty liver has 
lower mean CT radiodensity than the spleen, the liver-to-spleen attenuation ratio is used as an index 
of liver fat, with increases in the ratio indicating reduced hepatic steatosis. We will also assess changes 
in serum liver transaminases to complement the CT results. 
-      Also, a single slice of the abdomen at the level of L4/L5 disc space will be selected and will be used for 
the measurement of VAT and SAT.  
-      Dr. Ansari-Gilani, a graduate from a Body Fellowship from Washington University, will oversee 
standardization of the images at both sites with the use of phantoms, will be the central reader for all 
scans, and will be blinded to clinical and treatment characteristics. Dr. McComsey has extensively used 
both DXA and CT scans in prior HIV studies.  
 
-      Pericardial fat content and density will be measured by non-contrast, chest CT scan, as previously 
described.18,46 The effect of GLP-1RA treatment on pericardial fat in HIV is unknown, as are the 
relationships between changes in pericardial fat and changes in insulin resistance and VAT. Thus, 
pericardial fat measurements will add novel and informative data.  
-        A noncontrast electrocardiogram-gated low-dose cardiac computed tomography (CT) for calcium 
scoring will be done in all patients. Images will be used to measure the pericardial fat by single reader 
(Dr. Ansari-Gilani) who will be blinded to randomization arm and subject characteristics.  

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- 
Resting energy expenditure will be assessed using handheld, portable, indirect calorimetry (Medgem 
by HealtheTech, now part of MicroLife Corporation). Participants will be instructed to come fasting 
from food (≥12h) and tobacco-/caffeine-free (>4h). A single-use mouthpiece and nose clip will be 
used, and participants will be instructed to breathe through their mouths into the self-calibrating 
Medgem device. Oxygen consumption (VO2) will be measured for 10 minutes to ensure achievement 
of a steady state, and energy expenditure will be calculated by the Weir equation.125 We have 
previously shown that REE is elevated in ART-naïve women with HIV and continues to be elevated 
even with effective ART and virologic suppression,126 suggesting an effect of HIV infection itself. Thus, 
this measurement will be particularly informative in the context of GLP-1RA treatment.  
 
- 
Natriuretic peptides (BNP and ANP) will be measured to help elucidate a potential mechanism by 
which GLP-1RAs may affect the metabolic endpoints measured in this proposal. ANP decreases blood 
pressure and cardiac hypertrophy, while BNP acts to reduce ventricular fibrosis. We have shown in a 
previous HIV study that BNP is independently associated with several CVD markers.127  
 
- 
Adipokines (leptin, adiponectin, resistin and visfatin) will be measured as previously described128 to 
inform us on the potential mechanism by which GLP-1RAs may affect VAT and inflammation markers. 
 
- 
Gut hormones will be measured from blood and collected during a 4-hour, mixed-meal tolerance test 
(MMTT). After fasting (≥12h), participants will be asked to drink an Ensure Plus (vanilla-flavored) 
nutritional supplement (5mL/kg of participant’s screening body weight). If participants have a milk 
intolerance this test will NOT be obtained due to ensure being a milk based product. Blood samples 
will be obtained via peripheral intravenous catheter 15 minutes before consumption, immediately 
prior to consumption, and then at 20, 40, 60, 90, 120, 180, and 240 minutes after consumption for 
measurement of glucose, insulin, GLP-1, GIP, glucagon, and C-peptide. Blood will be collected into 
tubes containing DPP4 inhibitor, EDTA and trasylol and centrifuged immediately in a refrigerated 
centrifuge. Plasma samples will be processed, aliquoted into several aliquots (gut hormones, due to 
breakdown in the thawing process, should be assayed in aliquots thawed just once), and immediately 
frozen. Blood will be batched and sent to Dr. Egan at the Diabetes Section of the National Institute of 
Aging for measurements of gut hormones, as previously described.129,130 Blood glucose levels will also 
be measured and monitored in real-time using Nova Biomedical STATStrip glucometer. A 4-hour 
follow-up period is necessary, as incretin hormones may be elevated for ≥3.5 hours after a meal. 
Participants will be given a meal after the test. As previously discussed, this study will be the first to 
measure GLP-1 or GIP in the setting of HIV-associated lipohypertrophy. Like GLP-1, GIP is secreted in 
the gut in response to dietary fat and glucose and is involved in adipocyte metabolism. Specifically, it 
enhances insulin-stimulated incorporation of fatty acids into triglycerides, stimulates lipoprotein 
lipase activity, and modulates fatty acid synthesis.131,132 GIP treatment has been shown to reduce 
obesity-induced adipose tissue inflammation and improve insulin sensitivity in mice.133  
 
- 
Monocyte immune activation (sCD14 and sCD163) will be measured by ELISA (R&D Systems), which 
correlates with coronary calcifications,113 non-calcified coronary plaques,134 and arterial 
inflammation135 in HIV and has been shown to decrease significantly as early as 18-24 weeks after a 
successful intervention.  
 
- 
Systemic inflammation will be assessed by measuring select markers that we have previously shown 
are associated with co-morbidities in HIV38,39,136 and are relevant to adipose tissue, insulin resistance, 
and CVD. hsCRP, IL-6, sTNFR-I, and sTNFR-II will be measured by ELISA (R&D Systems).  

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- 
Standard lipoprotein profile and oxidized-LDL levels will be measured in a fasting state by ELISA 
(Mercodia).137,138  
 
- 
Insulin resistance and glucose tolerance will be assessed by measuring fasting insulin and glucose and 
then again 2 hours after administration of an oral glucose load of 75 grams, as previously described.139 
We will also calculate HOMA-IR, a reproducible index of insulin resistance.140  
 
- 
Gut integrity and microbial translocation will be measured to explore whether the improvement in 
VAT associated with GLP-1RA treatment is independent of changes in gut barrier integrity. We will use 
ELISA to measure plasma levels of LPS (a marker of microbial translocation; R&D Systems), intestinal 
fatty acid binding protein (I-FABP; a marker of enterocyte damage; R&D Systems),141 and zonulin-1 (a 
protein that modulate the permeability between cells of the digestive tract wall;142 Immundiagnostik). 
In HIV-uninfected populations, increased zonulin-1 levels are found in conditions associated with 
heightened inflammation and had been linked to obesity, insulin resistance, and liver steatosis.143,144 
In HIV, increased levels of zonulin have been linked to increased mortality.145  
 
- 
Pulse wave velocity is a non-invasive measure of arterial stiffness that uses SphygmoCor technology. 
PWV involves the detection of pulse vibrations with the use of a tonometry pen pressed against the 
skin146,147 and is associated with CVD events.97 Augmentation index, another measure of arterial 
stiffness that correlates with CVD risk,98 will also be measured, normalized to a heart rate of 75. The 
investigators have used PWV in other studies,148 and previous in-house data at both sites show 
excellent measurement error (CV 3-4%). Designated technicians will perform the PWV tests with 
SphygmoCor equipment (CPVH model, v.9 software). 
 
- 
Endothelial function (EndoPAT): a non-invasive, user-independent technique using the FDA-
approved EndoPAT2000 (Itamar Medical Ltd, Israel) provides a reliable and reproducible assessment 
of endothelial function that predicts atherosclerosis and CVD events. Using modified 
plethysmographic biosensors, the PAT signal is measured from the fingertip by measuring arterial 
pulsatile volume changes. A cuff is inflated around the upper arm to obstruct flow and released. The 
surge of blood flow causes endothelial dependent FMD, manifested as a reactive hyperemia. The 
EndoPAT® calculate the RHI, the ratio of digital pulse volume during reactive hyperemia and the 
baseline. In addition to the RHI, we will obtain peripheral Aix, adjusted for HR of 75, which will be 
compared to central Aix obtained with PWV. We have excellent track record in performing vascular 
studies, and carefully control for factors that could influence endoPAT; studies are performed at 24 C 
with the patient resting quietly. Subjects will be fasting, without smoking, caffeine, and exercise for 
>4 hours. 
- 
Skin AGE Measurements: There has been evidence that diet effects advanced glycation end 
products (AGE) therefore Skin AGE measurements will be obtained. This study has designated the 
AGE Reader instrument (manufactured by Diagnoptics Technologies B.V. located in Groningen 
Netherlands) as having a “nonsignificant risk” to study participants. Some individuals are known to 
have, or are at risk for, photosensitivity reactions (e.g., sensitive to ultraviolet light, or taking 
medication known to cause photosensitivity). We will exclude from the study those potential 
participants who report having these risk factors. However, there is a negligible risk that these 
participants might not be known until they develop a reaction.  
 

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- 
Additional plasma, PBMCs, serum, urine, and stool will be collected and frozen for future 
measurements of cellular immune activation, CVD and metabolic markers, other inflammatory or 
oxidative factors. Optional genetic material will be stored.  
 
- 
In extreme situations where the participant is unable to come to the clinic for a weekly injection and 
the participant’s home is within reasonable driving distance from the clinic to allow the IP to be 
administered within the required 30 minutes of being prepared by the pharmacy, with the 
participant’s consent, the study nurse and second study personnel will go to the participant’s 
residence to administer the injection. Participants will be informed that study staff who are visiting 
the participant’s residence for this purpose are legally required to report any witnessed or suspected 
elder or child abuse or other suspicious activities to the appropriate authorities if they observe them. 
In home injections will only be given if a participant is physically unable to come to the study clinic. 
 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
Our exclusion criteria protect certain vulnerable people from potential side effects associated with GLP-
1RAs. We will exclude anyone with diabetes or renal dysfunction, a history of alcohol abuse, pancreatitis, 
thyroid cancer, or a family/personal history of medullary thyroid carcinoma or MEN type 2. We will also 
exclude anyone with excessive alcohol intake, an elevated lipase or liver enzymes, active gastrointestinal 
symptoms, a hemoglobin <10 g/dL, as described in the inclusion/exclusion criteria. Pregnancy and 
lactation are exclusionary.  
 
 
Once enrolled in the study, participants will be monitored very closely for any side effects of the study 
drug and adverse events. They will be seen weekly and safety monitoring will occur at each of these study 
visits including evaluations for clinical signs and symptoms suggestive of any concerning conditions, such 
as pancreatitis, thyroid dysfunction, etc. At the comprehensive study visits, participants will be monitored 
closely for sign/symptoms and any adverse events associated with the procedures (e.g. during and after 
blood draws, while fasting, etc.). 
 
Participants’ blood will be measured for serial safety laboratory tests at week 14, 20, 26, 32 and 56 study 
visits, including comprehensive metabolic panels, which will include liver function tests, creatinine, lipase, 
among others. Urine pregnancy tests will be done on females of reproductive potential as outlined in the 
schedule of activities. HIV-1 RNA and CD4/CD8 will also be measured as part of routine care every 12 
weeks. 
 
We will educate participants about important signs/symptoms, and they will be instructed to contact a 
member of the study team (24 hours/day by pager) with any concerns. Participants with any of 
sign/symptoms concerning for this diagnosis will have his/her study drug withheld until a diagnosis is 
made. Participants will be permanently taken off study drug when indicated, as outlined in Section 7.1. 
Our interventional portion of the study is short (32 weeks only), and we will use an FDA-approved dose of 
semaglutide. 
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 

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Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the participant and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
 
The following guidelines will be used to describe severity of adverse events:  
 
1. 
Mild – Events require minimal or no treatment and do not interfere with the participant’s 
daily activities.  
2. 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
3. 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) will have their relationship to study intervention assessed by the study staff who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. The 
degree of certainty about causality will be graded using the categories below: 
 
1. 
Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study intervention 
administration and cannot be explained by concurrent disease or other drugs or chemicals. 
The response to withdrawal of the study intervention (dechallenge) should be clinically 
plausible. The event must be pharmacologically or phenomenologically definitive, with use of 
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2. 
Possibly Related – There is evidence to suggest a causal relationship, and the influence of 
other factors is unlikely. The clinical event, including an abnormal laboratory test result, 
occurs within a reasonable time after administration of the study intervention, is unlikely to 
be attributed to concurrent disease or other drugs or chemicals, and follows a clinically 
reasonable response on withdrawal (dechallenge). Rechallenge information is not required to 
fulfill this definition. Or, there is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly related” 
soon after discovery, it can be flagged as requiring more information and later be upgraded 
to “definitely related” as appropriate. 
3. 
Not related – A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to study intervention administration makes a causal relationship improbable 
(e.g., the event did not occur within a reasonable time after administration of the study 
intervention) and in which other drugs or chemicals or underlying disease provides plausible 
explanations (e.g., the participant’s clinical condition, other concomitant treatments). Or, the 
AE is completely independent of study intervention administration, and/or evidence exists 
that the event is definitely related to another etiology. [There must be an alternative, 
definitive etiology documented by the clinician.] 
 
 
8.3.3.3 EXPECTEDNESS  
 
The principal investigator will be responsible for determining whether an adverse event (AE) is expected 
or unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described for the study intervention. 
 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
research staff during study visits and interviews of a study participant presenting for medical care, or upon 
review by a study monitor. Principal Investigators and study team will review all safety labs and clinical 
assessments on a continual basis. All adverse events will be recorded in case report forms and graded per 
NIH guidelines. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of onset, 
clinician’s assessment of severity, relationship to study product (assessed by principal investigator), and 
time of resolution/stabilization of the event. All AEs occurring while on study will be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time 
during the study, it will be recorded as an AE.  
 

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Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
Research staff will record all reportable events and inform directly the Principal Investigators with start 
dates occurring any time after informed consent is obtained until 7 (for non-serious AEs) or 30 days (for 
SAEs) after the last day of study participation.  At each study visit, the investigator will inquire about the 
occurrence of AE/SAEs since the last visit.  Events will be followed for outcome information until resolution 
or stabilization. 
 
All laboratory results will be assessed by the study team. Abnormal laboratory values are defined as values 
outside the defined reference range and will be graded as per the NIH laboratory grading scale. Grade 1 
and 2 laboratory values will be discussed with the PI within one week and any Grade >2 laboratory value 
will be discussed in real-time with the PI. When deemed clinically-necessary, the participant will be 
contacted and brought back for repeat testing within 1 week. Critical values will be repeated without delay 
when deemed clinically-necessary. The participant’s primary provider will be notified within one week if 
the participant had given prior permission for release of medical information.  
 
8.3.5 ADVERSE EVENT REPORTING  
Principal Investigators and study team will review all safety labs and clinical assessments on a continual 
basis. All adverse events will be recorded in case report forms and graded per NIH guidelines. All >Grade 
1 adverse events deemed possibly-, probably- or definitely-related to study participation will be reported 
to the local IRBs yearly and to the DSMB and will be presented in scientific publications. All >Grade 2 
adverse events deemed to be possibly-, probably- or definitely-related to study participation will be 
reported to both institutions, the DSMB, NIH, and FDA within one week in writing. DSMB findings will be 
submitted to the local IRBs with the yearly continuing review (or ad hoc, when indicated) in a report 
prepared by the PIs and study staff and will include enrollment and drop-out rates, protocol deviations, 
participant symptoms, and review of clinical and laboratory results. The PIs will notify the NIH, FDA, and 
DSMB of any action recommended by the IRBs that may affect the conduct of the trial. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
Principal Investigators and study team will review all safety labs and clinical assessments on a continual 
basis. All adverse events will be recorded in case report forms and graded per NIH guidelines. All serious 
adverse events deemed to be possibly-, probably- or definitely-related to study participation will be 
reported to both institutions, the DSMB, NIH, and FDA within one week in writing. DSMB findings will be 
submitted to the local IRBs with the yearly continuing review (or ad hoc, when indicated) in a report 
prepared by the PIs and study staff and will include enrollment and drop-out rates, protocol deviations, 
participant symptoms, and review of clinical and laboratory results. The PIs will notify the NIH, FDA, and 
DSMB of any action recommended by the IRBs that may affect the conduct of the trial. 
 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 

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The study team will contact a participant within one week with any clinical and laboratory result Grade 1-
2 that is deemed clinically-relevant. Participants will be contacted immediately when deemed clinically-
necessary. With permission from the participant, any relevant information will be sent to his/her PCP or 
emergency department, and the PI will contact the provider directly.  
Any incidental finding deemed clinically-relevant will be discussed with the participant, so that the 
participant can obtain medical treatment from his/her PCP or local emergency department. With 
permission from the participant, any relevant information will be sent to his/her PCP or emergency 
department, and the PI will contact the provider directly.  
If there are any adverse events or study findings that may impact the safety of participants or change their 
willingness to participate in the trial, participants will be notified within one week.  
 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
 
Not applicable. 
 
8.3.9 REPORTING OF PREGNANCY  
If a female participant has a confirmed pregnancy, she will immediately be taken off study immediately. 
This event will be reported to the DSMB, IRB and NIH as required by local and federal regulations.   
 
8.4 
UNANTICIPATED PROBLEMS 
 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
  
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
- 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-approved 
research protocol and informed consent document; and (b) the characteristics of the participant 
population being studied; 
- 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
- 
Suggests that the research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  

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Incidents or events that meet the OHRP criteria for unanticipated problems will initiate the creation and 
completion of an unanticipated problem report form that will be submitted to DSMB, IRB, FDA, and NIH 
as outlined. The following information will be included:  
- 
Appropriate identifying information for the research protocol, such as the title, investigator’s name, 
and the IRB project number; 
- 
A detailed description of the adverse event, incident, experience, or outcome;  
- 
An explanation of the basis for determining that the adverse event, incident, experience, or outcome 
represents an unanticipated problem;  
- 
A description of any changes to the protocol or other corrective actions that have been taken or are 
proposed in response to the unanticipated problem. 
 
To satisfy the requirement for prompt reporting, unanticipated problems will be reported using the 
following timeline:   
- 
Unanticipated problems that are serious adverse events will be reported to the IRB, DSMB, FDA, and 
NIH within 7 days of the investigator becoming aware of the event.  
- 
Any other unanticipated problem will be reported to the IRB, DSMB, and NCCIH within 14 days of the 
investigator becoming aware of the problem.  
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Participants will be directly contacted by the study team and brought back for assessment, if necessary. 
 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
The primary objective of this innovative, prospective, longitudinal RCT study is to determine the efficacy 
of GLP-1RAs in treating lipohypertrophy among non-diabetic people living with HIV (PLWH) by reducing 
fat accumulation and ectopic fat deposition, altering adipokine levels, improving endothelial function and 
arterial stiffness, down-regulating key pro-inflammatory cytokines and immune activation without 
modifying microbial translocation and gut integrity markers (Aims 1 & 2).  
 
9.2 
SAMPLE SIZE DETERMINATION 
The following sample size estimation and power analysis are based on the significance level 0.05, 90% 
power, and 20% dropout adjustment. We hypothesize that after the GLP-1RA treatment the primary 
outcomes of interest (VAT, hsCRP) will be improved in both groups of participants: PLWH and HIV-
uninfected controls. Based on Li,42 we assume that, at baseline, the mean ±SD of VAT in PLWH is 277.80 ± 
68.75 cm2. Using Frison119 change method for repeated measures design, we estimated the sample size 
based on the difference in the two groups of the mean change of the post-treatment measurements at 
week 32 assuming that correlation between repeated measurements is 0.65. Conservatively assuming a 
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participants per arm, in a longitudinal measures design with 3 longitudinal measurements, can be 
detected with 90% power. Similarly, based on Bunck,72 we assume that the average hsCRP is 1.81 ± 1.37 
mg/L at baseline and 1.15 ± 1.20 mg/L at 32 weeks. A mean difference of 0.66 mg/L (1.81–1.15) in hsCRP 
level change between two groups with 43 participants in each arm can be detected with >90% power. 
Sample size was inflated to 52 per arm to account for a conservative 20% loss-to-follow up/missing data. 
We hypothesize that there will be equivalent effects of GLP-1RA treatment on the HIV-uninfected 
participants as those PLWH, which suggests equal number of enrollment in both groups. Therefore, for 
the two-parallel studies (PLWH and controls), we will enroll total 104 + 104 = 208 participants. The sample 
size estimation was performed using STATA 12.0.120 
 
9.3 
POPULATIONS FOR ANALYSES 
104 PLWH (52 active; 52 placebo) will be studied for a total of 56 weeks. During this study period, outcome 
variables and other measurements will be assessed at various time points. To know their trajectories after 
discontinuing GLP-1RA treatment, several measurements will also be assessed at week 56. All outcome 
variables will be analyzed, and estimated values will be portrayed graphically.  
Tests for inequality between the treated and placebo groups at 0, 32, and 56 weeks will be performed 
using likelihood ratio tests with multiple testing corrections using the Benjamini-Hochberg procedure.116 
If there are large numbers of missing values, we will estimate the parameters by utilizing the "pattern 
mixture model,” which assumes liner mixed model. In the presence of outliers and informative dropouts, 
we will consider using a likelihood-based method developed by Sinha and Sattar118 for analyzing 
incomplete longitudinal continuous response measurements with non-ignorable missing and outliers. 
Alternatively, we may use generalized estimating equation with doubly-robust approach; however, this 
will be avoided, if possible, because it will lead to decreased power.  
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
Study variables, outcomes, and covariates will be summarized using mean, standard deviation, median, 
and interquartile range cross-sectional and longitudinally by group. The distributions of variables will be 
examined and necessary transformations (e.g. Box-Cox transformation) will be used to achieve normality 
with results back transformed for ease of interpretation. The outcome variables are in continuous scale; 
thus, flexible linear mixed-effects models115 or a similar repeated measures analysis model (e.g., 
generalized estimating equations) will be used in analyzing the response trajectories and the benefits of 
the treatment. We will collect information on the covariates: demographics, health history, and potential 
moderators including: medication history, dietary and physical activity, HIV RNA, CD4, and weight/BMI. 
The effects of treatment may be adjusted for these covariates and moderators through the linear mixed 
effect model analyses.  
For reproducibility of the results, the data quality will be reviewed rigorously, and necessary 
transformations performed to satisfy assumptions related to residuals for parametric models. Basic 
descriptive statistics will be used to summarize outcomes and covariates within each group of 
participants.  
Statistical analysis will be conducted using software Stata 15.0 software. 

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9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
To depict the effects of treatment, summary statistics and predicted values of longitudinally-measured 
outcome variables will be presented graphically. Models for longitudinally-measured outcome variables, 
analysis method, and computation of power will be conducted. Two-sided hypothesis tests will be 
performed assuming a 0.05 level of significance. Type I error rate in multiple comparisons will be 
controlled by the step-up Benjamini and Hochberg procedure116 (for small number of comparisons, 
Bonferroni will be used). However, according to the American Statistical Association statement on p-value, 
we will emphasize on the magnitude of the outcome variable differences between the groups, and effect 
sizes in terms of nonzero beta coefficients and its 95% CI rather than adjusted p-values117.  
To evaluate the effects of GLP-1RA treatment, we will analyze primary outcome variables (VAT, hsCRP, 
and EndoPat) using flexible linear mixed models or a similar repeated measure analysis model (e.g., 
generalized estimating equations (GEE)). If an outcome distribution is highly skewed and no existing 
transformation can make it symmetric, we may apply quantile (median) regression for estimating the 
effects of the treatment. If an outcome distribution is highly skewed and no existing transformation can 
make it symmetric, we may apply quantile (median) regression for estimating the effects of the treatment. 
Let Yij denote an outcome variable from the ith participant at the jth week, where i=1, 2, ..., 104 HIV-
infected participants; j=0 (entry), 32 weeks. Define Tij to be the week when the measurements are 
obtained from participant i. The repeated measures (e.g., linear mixed) model for the outcome Yij will be 
developed. The model may include vectors of covariates, moderators, intervention or the GLP-1RA 
treatment, and the vectors of random effects 𝑣𝑣𝑖𝑖= (𝑣𝑣0𝑖𝑖, 𝑣𝑣1𝑖𝑖)′ are assumed to be independent multivariate 
normal with mean vector 0 and covariance matrix, 𝐺𝐺(𝜃𝜃) = 𝐺𝐺(𝜎𝜎𝑣𝑣11, 𝜎𝜎𝑣𝑣12, 𝜎𝜎𝑣𝑣22). The error term in the 
model is assumed to be distributed as normal(0, 𝜎𝜎2), and 𝐺𝐺 is assumed to be an unstructured covariance 
matrix. From the fitted linear models, we will delineate the predicted outcome variables, association 
between outcomes, and GLP-1RA treatment. The model parameters will be estimated by the method of 
(restricted) maximum likelihood or method of moments if GEE is used. Likelihood ratio tests will be used 
to compare overall mean curves for the groups. Tests for inequality between the treated and placebo 
groups at 0, 32, and 56 weeks will be performed using likelihood ratio tests with multiple testing 
corrections using the Benjamini-Hochberg procedure.116 If there are large numbers of missing values (i.e., 
non-ignorable missing), we will estimate the parameters by utilizing the "pattern mixture model,” which 
assumes liner mixed model. In the presence of outliers and informative dropouts, we will consider using 
a likelihood-based method developed by Sinha and Sattar118 for analyzing incomplete longitudinal 
continuous response measurements with non-ignorable missing and outliers. Alternatively, we may use 
generalized estimating equation with doubly-robust approach; however, this will be avoided, if possible, 
because it will lead to decreased power.  
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Refer to section 9.4.2 above. 
 
9.4.4 SAFETY ANALYSES 
 
Each participant will have all graded laboratory and clinical adverse events listed in his/her study chart 
and will include start/stop dates, severity, and relationship to study intervention, expectedness, outcome, 
and duration. Graded clinical and laboratory adverse events will then be listed for all participants 

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collectively and summarized with frequency and percent. Adverse events that occur more than once or 
with varying degrees of severity in the same participant will be identified, and analyzes will be repeated 
including only one adverse event per participant (the one with the highest grade or longest duration will 
be selected). Adverse events leading to premature discontinuation from the study intervention and 
serious treatment-emergent AEs will be highlighted. Adverse events will also be summarized by study 
population (HIV and controls) and frequencies between the two groups will be compared. The statistician 
will also prepare blinded reports based on randomization arm (for all participants and stratified by HIV 
status) to determine differences in adverse event frequency and severity between study drug and 
placebo.  
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
We will collect information on the covariates: demographics, health history, and potential moderators 
including: medication history, dietary and physical activity, HIV RNA, CD4, and weight/BMI. The effects of 
treatment will be adjusted for these covariates and moderators through the linear mixed effect model 
analyses. For reproducibility of the results, the data quality will be reviewed rigorously, and necessary 
transformations performed to satisfy assumptions related to residuals for parametric models. Basic 
descriptive statistics will be used to summarize outcomes and covariates within each group of 
participants.  
 
9.4.6 PLANNED INTERIM ANALYSES  
 
Not applicable. 
 
 
 
9.4.7 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Individual participant data will be listed both by measure and time point.  
 
9.4.8 EXPLORATORY ANALYSES 
 
Not applicable. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
Consent forms describing in detail the study intervention, study procedures, risks, HIPPA/privacy 
policies, and study staff information will be given to all participants.  

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10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
 
Consent forms will be reviewed and approved by the institutional review board. Potential participants will 
be asked to visit the clinic at least once to be screened and ensure that they meet the requirements for 
entry into the study and are interested in study participation. Potential participants will provide written 
informed consent before any study procedure can occur. The site PI or designated member of the study 
team will conduct the informed consent process. The participant will be asked to read and review the 
document carefully. The PI or designated member of the study team will then explain the research study 
to the participant and answer any questions that may arise. A verbal explanation will be provided in terms 
suited to the participant’s comprehension of the purposes, procedures, and potential risks of the study 
and of their rights as research participants. Participants will have the opportunity to further review the 
written consent form and ask questions prior to signing. The participants will have the opportunity to 
discuss the study with their family or surrogates or think about it prior to agreeing to participate. 
Participants will be informed that participation is voluntary and that they may withdraw from the study 
at any time, without prejudice. If he/she agrees to study participation, the informed consent form will be 
signed by both the participant and study team member. The site PI or designated member of the study 
team will complete a checklist indicating date and time the consent was signed, who was present, version 
date, and if a copy was provided to participant that will be filed in the participant’s chart. A copy of the 
informed consent document will be given to the participants for their records. The site PI will review all 
signed consent forms for the respective site.   
Illiterate Subjects: Subjects with all levels of literacy will be eligible for this study.  The consent document 
will be read to those volunteers with less than an 8th grade equivalent level of literacy.  Subsequently, the 
informed consent will be signed by the volunteer making their mark in the signature section in order to 
document their understanding.  A witness will be present to confirm the consent process has taken place.  
Both the witness and person conducting the consent process will sign and date the consent.  The 
investigator obtaining consent will ask each subject to reiterate what will be required from them, risks 
and benefits, and their rights as a participant in order to ensure their full understanding of the study.  
Non-English-Speaking Subjects: Subjects who do not understand or speak English will also be eligible for 
this study. The consent form will be read to those non-English-speaking study candidates in their primary 
language by a translator. A witness (who speaks English and the study subject’s language) will be present 
to confirm the consent process has taken place. Both the witness and person conducting the consent 
process will sign and date the consent. The investigator obtaining consent will ask the study candidate via 
the translator to reiterate what will be required from him/her, risks and benefits, and his/her rights as a 
participant in order to ensure their full understanding of the study. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification documenting the reason for study suspension or termination will be provided 
by the suspending or terminating party to study participants, investigators, NIH, and FDA. If the study is 
prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study 
participants, the Institutional Review Board (IRB), and NIH and will provide the reason(s) for the 
termination or suspension. Study participants will be contacted, as applicable, and be informed of changes 
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Circumstances that may warrant termination or suspension include, but are not limited to: 
 
1. Determination of unexpected, significant, or unacceptable risk to participants 
2. Insufficient compliance to protocol requirements 
3. At the discretion of the FDA, IRB, or NIH 
4. Data that are not sufficiently complete and/or evaluable 
5. Determination that the primary endpoint has been met 
6. Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed and 
satisfy the IRB, NIH, and FDA. 
 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
Efforts will be made to keep all personal information confidential. All research activities will be conducted 
in as private a setting as possible. Only IRB-approved research staff will have access to identifiable private 
information about the participants. Patient clinical and laboratory data will be collected on standardized 
forms which will be kept in locked filling cabinets in locked offices and/or stored on HIPAA-compliant, 
password-protected, cloud-based storage system “Box” and/or REDcap and only accessible to study staff. 
Each participant will be assigned a coded number, and this number will be used to identify the participant. 
All laboratory specimens, evaluation forms, reports, and other records will be identified by coded number 
only to maintain participant privacy. All computer entry and networking programs will be done with coded 
numbers only. Any material or data sent to non-study staff personnel will contain only de-identified 
information. No names or personal information will be used to identify the subjects. Clinical information 
will not be released to the participant’s private physician, clinic, or any other entity without permission of 
the subject, except as necessary for monitoring by the IRB, FDA, NIH, or as required by law. Release of 
information will be documented from subjects before requesting any medical records from outside clinics, 
and associated documents will only be sent/received from HIPAA-compliant, secured fax lines. Study staff 
will only talk to participants or participants’ representatives when phone calls are made for recruitment, 
retention, or adherence reasons, and any message left will have no mention of HIV. Recruitment material 
or any information given to participants (e.g., date reminders for study visits) will not mention HIV. Any 
publication of this study will not use the participant’s name or any personal identifiers. Both study sites 
will ensure that appropriate measures are taken to protect the privacy and confidentiality of all 
personally-identifiable health information (PHI) for which it is responsible. The proposed studies will 
include compliance with all regulations set forth by the HIPAA Privacy Rule, as well as with existing State 
and Federal laws pertaining to PHI.  
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
With the participant’s approval and as approved by local Institutional Review Boards (IRBs), de-identified 
biological samples of plasma, PBMCs, serum, urine, and stool will be collected and frozen at –80°C for 
future measurements of cellular immune activation, CVD and metabolic markers, other inflammatory or 
oxidative factors. Optional genetic material will be stored with participant approval.  
 

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During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage may not be possible after the study is completed.  
 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Principal Investigator 
Grace A McComsey, MD, FIDSA  
Professor of Pediatrics and Medicine 
Allison Ross Eckard, MD, FIDSA, AAHIVS 
Associate Professor of Pediatrics and Medicine 
Case Western Reserve University 
 
Medical University of South Carolina 
Office | LKSD 1400 Mail Stop | LKSD 7061 
11100 Euclid Ave. Cleveland, OH 44106 
 
135 Rutledge Ave, Ste 1217, MSC 752 
Charleston, SC 29425-7520 
 
216-844-5936 
 
843-876-1920 
Grace.McComsey@UHhospitals.org 
eckarda@musc.edu 
The Steering Committee, comprised of the PIs, key personnel, and consultants will meet every 4 months, 
or more frequently if necessary, by conference call to discuss study progress, review interim data, and 
delineate plans for the next 6 months. The Steering Committee will help oversee decisions on minor 
changes in research direction, publications, data sharing, and reallocation of funds, if necessary. 
 
10.1.6 SAFETY OVERSIGHT 
A data and safety monitoring board (DSMB) was established to include three physicians (one HIV 
physician, one endocrinologist, one cardiologist) and a statistician. All DSMB members are independent 
of the study team. The DSMB will review interim data to detect evidence of adverse events to determine 
if the trial should continue as originally designed, should be changed, or even stopped based on the data. 
The DSMB will evaluate the progress of the trial, including periodic assessments of the recruitment goals, 
protocol adherence, accrual and retention of participants. The DSMB will also function to review and 
approve plans for data and safety monitoring for this trial, review data on a timely basis and ensure proper 
conduct and progress of study, review credentials of investigator and project staff, make 
recommendations to PIs and staff regarding issues of concern, and address adverse events. The DSMB will 
meet every 6 months (or earlier as needed) in Cleveland, Ohio or by phone conferences to review study 
protocols, progress, and safety data. Meetings will be held in an open format, except if privileged data are 
discussed. The DSMB will protect confidentiality of the study participants.  
PIs and study team will review all safety labs and clinical assessments on a continual basis. As previously 
described, all adverse events will be recorded in case report forms and graded per NIH guidelines. All 
>Grade 1 adverse events deemed possibly-, probably- or definitely-related to study participation will be 
reported to the local IRBs yearly and to the DSMB as described above and will be presented in scientific 
publications. All >Grade 2 adverse events deemed to be possibly-, probably- or definitely-related to study 
participation will be reported to both institutions, the DSMB, NIH, and FDA within one week in writing. 
DSMB findings will be submitted to the local IRBs with the yearly continuing review (or ad hoc, when 
indicated) in a report prepared by the PIs and study staff and will include enrollment and drop-out rates, 

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protocol deviations, participant symptoms, and review of clinical and laboratory results. The PIs will notify 
the NIH, FDA, and DSMB of any action recommended by the IRBs that may affect the conduct of the trial. 
The PIs will review recommendations from the Steering Committee and all other relevant data available 
to reach informed decisions. 
 
10.1.7 CLINICAL MONITORING 
 
Clinical monitoring will occur at each respective site by way of the local institution’s office of clinical 
research. Study staff will ask a designated official to perform an audit after the first 1-3 subjects have been 
enrolled to ensure that the conduction of the trial is in compliance with appropriate protocols and 
regulations. The monitor will compile a written report that will describe any issues and a point-by-point 
list of addressable items. The study team will have 30 days to address any issues and provide a written 
account of how each item was corrected. A complete report will be submitted to the IRB, the office of 
clinical research, and any other appropriate local or federal agency.  
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Each clinical site will perform internal quality management of study conduct, data and biological specimen 
collection, documentation and completion. An individualized quality management plan will be developed 
to describe a site’s quality management. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is 
conducted and data are generated and biological specimens are collected, documented (recorded), and 
reported in compliance with the protocol, International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)).  
 
 
10.1.9 DATA HANDLING AND RECORD KEEPING.  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Clinical data will be collected systematically, captured onto standardized case report forms, and double-
entered into REDCap, a secure web-based application that provides case report forms, real-time data 
entry validation, audit trails, and a de-identified data export mechanism. Data entry fields will be 
programmed for required entry/range checks. Both the study coordinators and PIs will review all case 
report forms continually to check for basic problems such as missing data. Periodically, data will be 
exported from REDCap and reviewed systematically by the biostatistician for errors. Specimens will be 
obtained and processed according to standardized procedures. Blood samples will be processed and 
stored appropriately at each respective study site and will be batched for measurements of inflammation, 
gut integrity, gut hormones, BNPs, adipokines, and other metabolic markers.  
 

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Each participating site will maintain appropriate medical and research records for this trial, in compliance 
with ICH GCP and regulatory and institutional requirements for the protection of confidentiality of 
participants. As part of participating in a NIH-sponsored or NIH-affiliated study, each site will permit 
authorized representatives of the NIH, sponsor, and regulatory agencies to examine (and when permitted 
by applicable law, to copy) clinical records for the purposes of quality assurance reviews, audits, and 
evaluation of the study safety, progress, and data validity.  
 
 
10.1.9.2 STUDY RECORDS RETENTION  
  
Study documents will be retained for a length of time in accordance with local and federal regulations.  
 
 
10.1.10 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. 
Corrective actions will be developed by the site and implemented promptly.  
 
These practices will be consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
Protocol deviations will be identified by study staff, recorded on a standardized protocol deviation log, 
and reported to IRB, DSMB, FDA, and NIH as required by local and federal regulations. 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
Sharing of data generated by this project is an essential part of our proposed activities and will be carried 
out to comply with the NIH policy on Sharing Research Data Sharing. We wish to make our results available 
both to the community of scientists interested in HIV infection, immune activation and co-morbidities, as 
well as to people living with HIV infection. The data generated in this project will be presented at local, 
national and international conferences and published in peer-reviewed journals in a timely fashion. All 
final peer-reviewed manuscripts that arise from this project will be submitted to PubMed Central. The PI 
will also work with the institutions’ publicity teams to disseminate findings on their respective websites 
and LISTSERVS. The PIs will also reach out to several national HIV advocacy groups to further disseminate 
findings (NATAP.org; thebody.com; IFARA, etc.) The PI will work to facilitate any request made for data 
produced under this proposal upon publication of data, using standard, university-approved 
material/data transfer agreements.  
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
Any actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, or 
any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict 
of interest will be required to have such conflicts managed in a way that is appropriate to their 

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participation in the design and conduct of this trial.  The study leadership in conjunction with the NIH has 
established policies and procedures for all study group members to disclose all conflicts of interest and 
will establish a mechanism for the management of all reported dualities of interest. 
 
10.2 ADDITIONAL CONSIDERATIONS 
 
Not applicable. 
 
10.3 ABBREVIATIONS 
The list below includes abbreviations utilized in this template.  However, this list should be customized for 
each protocol (i.e., abbreviations not used should be removed and new abbreviations used should be 
added to this list). 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LSMEANS 
Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 

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MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
HIV 
human immunodeficiency virus 
PLWH 
People living with human immunodeficiency virus 
GLP1RA 
Glucagon like peptide-1 Receptor Agonist 
SC 
Subcutaneous 
LPS 
Lipopolysaccharide 
I-FABP 
Intestinal fatty acid binding proteins 
MMTT 
Mixed-meal tolerance test 
PWV 
Pulse Wave Velocity 
PHI 
personally-identifiable health information 
RCT 
Randomized controlled trial 
WC  
Waist circumference  
WHR 
Waist-hip ratio 
DXA 
DEXA Scan 
ART 
Antiretroviral Therapy 
 
 
 

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11 REFERENCES  
 
1. McComsey GA, Walker UA. Role of mitochondria in HIV lipoatrophy: insight into pathogenesis and 
potential therapies. Mitochondrion 2004; 4(2-3):111-118.  
2. McComsey G, Bai RK, Maa JF, Seekins D, Wong LJ. Extensive investigations of mitochondrial DNA 
genome in treated HIV-infected subjects: beyond mitochondrial DNA depletion. J Acquir Immune Defic 
Syndr 2005; 39(2):181-188.  
3. McComsey GA, Paulsen DM, Lonergan JT, Hessenthaler SM, Hoppel CL, Williams VC, et al. 
Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine 
with abacavir or zidovudine. AIDS 2005; 19(1):15-23.  
4. McComsey GA, Kitch D, Sax PE, Tebas P, Tierney C, Jahed NC, et al. Peripheral and central fat changes 
in subjects randomized to abacavir-lamivudine or tenofovir-emtricitabine with atazanavir-ritonavir or 
efavirenz: ACTG Study A5224s. Clin Infect Dis 2011; 53(2):185-196. 3165963.  
5. McComsey GA, Ward DJ, Hessenthaler SM, Sension MG, Shalit P, Lonergan JT, et al. Improvement in 
lipoatrophy associated with highly active antiretroviral therapy in human immunodeficiency virus-
infected patients switched from stavudine to abacavir or zidovudine: the results of the TARHEEL study. 
Clin Infect Dis 2004; 38(2):263-270.  
6. Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J 
Med 2005; 352(1):48-62.  
7. McComsey GA, Moser C, Currier J, Ribaudo HJ, Paczuski P, Dube MP, et al. Body Composition Changes 
After Initiation of Raltegravir or Protease Inhibitors: ACTG A5260s. Clin Infect Dis 2016; 62(7):853-862. 
PMC4787610.  
8. Bhagwat P, Ofotokun I, McComsey G, Brown T, Moser C, Sugar C, et al. Predictors of severe 
weight/body mass index gain following antiretroviral initiation, Abstract 695. In: Conference on 
Retroviruses and Opportunistic Infections. Seattle, WA; 2017. 
9. Thamer C, Machann J, Stefan N, Haap M, Schafer S, Brenner S, et al. High visceral fat mass and high 
liver fat are associated with resistance to lifestyle intervention. Obesity (Silver Spring) 2007; 15(2):531-
538.  
10. Targher G, Bertolini L, Padovani R, Rodella S, Tessari R, Zenari L, et al. Prevalence of nonalcoholic fatty 
liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes 
Care 2007; 30(5):1212-1218.  
11. Cherian S, Lopaschuk GD, Carvalho E. Cellular cross-talk between epicardial adipose tissue and 
myocardium in relation to the pathogenesis of cardiovascular disease. Am J Physiol Endocrinol Metab 
2012; 303(8):E937-949.  
12. Iacobellis G, Bianco AC. Epicardial adipose tissue: emerging physiological, pathophysiological and 
clinical features. Trends Endocrinol Metab 2011; 22(11):450-457.  
13. Sacks HS, Fain JN. Human epicardial fat: what is new and what is missing? Clin Exp Pharmacol Physiol 
2011; 38(12):879-887.  
14. Hirata Y, Tabata M, Kurobe H, Motoki T, Akaike M, Nishio C, et al. Coronary atherosclerosis is 
associated with macrophage polarization in epicardial adipose tissue. J Am Coll Cardiol 2011; 58(3):248-
255.  
15. Kremen J, Dolinkova M, Krajickova J, Blaha J, Anderlova K, Lacinova Z, et al. Increased subcutaneous 
and epicardial adipose tissue production of proinflammatory cytokines in cardiac surgery patients: 
possible role in postoperative insulin resistance. J Clin Endocrinol Metab 2006; 91(11):4620-4627.  

McComsey/Eckard GLP1RA-HIV-LH 
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50 
 
16. Iacobellis G, Ribaudo MC, Assael F, Vecci E, Tiberti C, Zappaterreno A, et al. Echocardiographic 
epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: 
a new indicator of cardiovascular risk. J Clin Endocrinol Metab 2003; 88(11):5163-5168.  
17. Rosito GA, Massaro JM, Hoffmann U, Ruberg FL, Mahabadi AA, Vasan RS, et al. Pericardial fat, visceral 
abdominal fat, cardiovascular disease risk factors, and vascular calcification in a community-based 
sample: the Framingham Heart Study. Circulation 2008; 117(5):605-613.  
18. Longenecker CT, Jiang Y, Yun CH, Debanne S, Funderburg NT, Lederman MM, et al. Perivascular fat, 
inflammation, and cardiovascular risk in HIV-infected patients on antiretroviral therapy. Int J Cardiol 
2013; 168(4):4039-4045. 3805774.  
19. Longenecker CT, Margevicius S, Liu Y, Schluchter MD, Yun CH, Bezerra HG, et al. Effect of Pericardial 
Fat Volume and Density on Markers of Insulin Resistance and Inflammation in Patients With Human 
Immunodeficiency Virus Infection. Am J Cardiol 2017; 120(8):1427-1433. PMC5614847.  
20. Crum-Cianflone N, Roediger MP, Eberly L, Headd M, Marconi V, Ganesan A, et al. Increasing rates of 
obesity among HIV-infected persons during the HIV epidemic. PLoS One 2010; 5(4):e10106. 
PMC2856157.  
21. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl 
peptidase-4 inhibitors in type 2 diabetes. Lancet 2006; 368(9548):1696-1705.  
22. Chia CW, Egan JM. Incretin-based therapies in type 2 diabetes mellitus. J Clin Endocrinol Metab 2008; 
93(10):3703-3716. 2579648.  
23. Yang M, Zhang L, Wang C, Liu H, Boden G, Yang G, et al. Liraglutide increases FGF-21 activity and 
insulin sensitivity in high fat diet and adiponectin knockdown induced insulin resistance. PLoS One 2012; 
7(11):e48392. 3495944.  
24. Chia CW, Egan JM. Role and development of GLP-1 receptor agonists in the management of diabetes. 
Diabetes Metab Syndr Obes 2009; 2:37. 2818016.  
25. Marre M, Shaw J, Brandle M, Bebakar WM, Kamaruddin NA, Strand J, et al. Liraglutide, a once-daily 
human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in 
glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 
diabetes (LEAD-1 SU). Diabet Med 2009; 26(3):268-278. 2871176.  
26. Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, et al. Efficacy and safety comparison of 
liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD 
(liraglutide effect and action in diabetes)-2 study. Diabetes Care 2009; 32(1):84-90. 2606836.  
27. Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, et al. 
Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, 
phase III, double-blind, parallel-treatment trial. Lancet 2009; 373(9662):473-481.  
28. Zinman B, Gerich J, Buse JB, Lewin A, Schwartz S, Raskin P, et al. Efficacy and safety of the human 
glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in 
patients with type 2 diabetes (LEAD-4 Met+TZD). Diabetes Care 2009; 32(7):1224-1230. 2699702.  
29. Russell-Jones D, Vaag A, Schmitz O, Sethi BK, Lalic N, Antic S, et al. Liraglutide vs insulin glargine and 
placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 
met+SU): a randomised controlled trial. Diabetologia 2009; 52(10):2046-2055. 2744824.  
30. Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, et al. Liraglutide once a day versus 
exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-
label trial (LEAD-6). Lancet 2009; 374(9683):39-47.  
31. Wysham CH, MacConell LA, Maggs DG, Zhou M, Griffin PS, Trautmann ME. Five-Year Efficacy and 
Safety Data of Exenatide Once Weekly: Long-term Results From the DURATION-1 Randomized Clinical 
Trial. Mayo Clin Proc 2015; 90(3):356-365.  

McComsey/Eckard GLP1RA-HIV-LH 
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32. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, et al. Semaglutide and Cardiovascular 
Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2016; 375(19):1834-1844.  
33. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and 
Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016; 375(4):311-322. PMC4985288.  
34. Bethel MA, Patel RA, Merrill P, Lokhnygina Y, Buse JB, Mentz RJ, et al. Cardiovascular outcomes with 
glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet 
Diabetes Endocrinol 2018; 6(2):105-113.  
35. Gagnon J, Sauve M, Zhao W, Stacey HM, Wiber SC, Bolz SS, et al. Chronic Exposure to TNFalpha Impairs 
Secretion of Glucagon-Like Peptide-1. Endocrinology 2015; 156(11):3950-3960.  
36. McComsey G, Moser C, Currier J, Ribaudo H, Paczuski P, Dube M, et al. Body Composition Changes 
after Initiation of Raltegravir or Protease Inhibitors-Oral Presentation. In: The 22th Conference on 
Retroviruses and Opportunistic Infections. Seattle, WA; 2015. 
37. McComsey GA, Kitch D, Daar ES, Tierney C, Jahed NC, Melbourne K, et al. Inflammation markers after 
randomization 
to 
abacavir/lamivudine 
or 
tenofovir/emtricitabine 
with 
efavirenz 
or 
atazanavir/ritonavir. AIDS 2012; 26(11):1371-1385.  
38. McComsey G, Kitch D, Sax P, Tierney C, Jahed N, Melbourne K, et al. Associations of Infammatory 
Markers with AIDS and non-AIDS Clinical Events after Initiation of Antiretroviral Therapy (ART):AIDS 
Clinical Trials Group A5224s, a substudy of ACTG A5202. In: The XIX International AIDS Conference 
Washington, DC; 2012. 
39. Ross AC, Rizk N, O'Riordan MA, Dogra V, El-Bejjani D, Storer N, et al. Relationship between 
inflammatory markers, endothelial activation markers, and carotid intima-media thickness in HIV-
infected patients receiving antiretroviral therapy. Clin Infect Dis 2009; 49(7):1119-1127.  
40. Brown TT, Tassiopoulos K, Bosch RJ, Shikuma C, McComsey GA. Association between systemic 
inflammation and incident diabetes in HIV-infected patients after initiation of antiretroviral therapy. 
Diabetes Care 2010; 33(10):2244-2249. 2945167.  
41. Astrup A, Rossner S, Van Gaal L, Rissanen A, Niskanen L, Al Hakim M, et al. Effects of liraglutide in the 
treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet 2009; 
374(9701):1606-1616.  
42. Li CJ, Yu Q, Yu P, Yu TL, Zhang QM, Lu S, et al. Changes in liraglutide-induced body composition are 
related to modifications in plasma cardiac natriuretic peptides levels in obese type 2 diabetic patients. 
Cardiovasc Diabetol 2014; 13:36. 3923001.  
43. Jendle J, Nauck MA, Matthews DR, Frid A, Hermansen K, During M, et al. Weight loss with liraglutide, 
a once-daily human glucagon-like peptide-1 analogue for type 2 diabetes treatment as monotherapy or 
added to metformin, is primarily as a result of a reduction in fat tissue. Diabetes Obes Metab 2009; 
11(12):1163-1172.  
44. Svegliati-Baroni G, Saccomanno S, Rychlicki C, Agostinelli L, De Minicis S, Candelaresi C, et al. Glucagon-
like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling 
alteration induced by a high-fat diet in nonalcoholic steatohepatitis. Liver Int 2011; 31(9):1285-1297.  
45. Cuthbertson DJ, Irwin A, Gardner CJ, Daousi C, Purewal T, Furlong N, et al. Improved glycaemia 
correlates with liver fat reduction in obese, type 2 diabetes, patients given glucagon-like peptide-1 (GLP-
1) receptor agonists. PLoS One 2012; 7(12):e50117. 3516516.  
46. Longenecker C, Liu Y, Schlucter M, McComsey G. Pericardial Fat Density: A Novel Marker of 
Cardiometabolic Risk in HIV Infection. In: The 22th Conference on Retroviruses and Opportunistic 
Infections. Seattle, WA; 2015. 
47. Nauck MA, Petrie JR, Sesti G, Mannucci E, Courreges JP, Lindegaard ML, et al. A Phase 2, Randomized, 
Dose-Finding Study of the Novel Once-Weekly Human GLP-1 Analog, Semaglutide, Compared With 

McComsey/Eckard GLP1RA-HIV-LH 
Version 10.0 
Protocol  
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52 
 
Placebo and Open-Label Liraglutide in Patients With Type 2 Diabetes. Diabetes Care 2016; 39(2):231-
241.  
48. Ahren B, Masmiquel L, Kumar H, Sargin M, Karsbol JD, Jacobsen SH, et al. Efficacy and safety of once-
weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or 
both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial. 
Lancet Diabetes Endocrinol 2017; 5(5):341-354.  
49. Ahmann AJ, Capehorn M, Charpentier G, Dotta F, Henkel E, Lingvay I, et al. Efficacy and Safety of Once-
Weekly Semaglutide Versus Exenatide ER in Subjects With Type 2 Diabetes (SUSTAIN 3): A 56-Week, 
Open-Label, Randomized Clinical Trial. Diabetes Care 2018; 41(2):258-266.  
50. Taylor SI. GLP-1 receptor agonists: differentiation within the class. Lancet Diabetes Endocrinol 2018; 
6(2):83-85. PMC5988583.  
51. Wysham C, Bergenstal R, Malloy J, Yan P, Walsh B, Malone J, et al. DURATION-2: efficacy and safety 
of switching from maximum daily sitagliptin or pioglitazone to once-weekly exenatide. Diabet Med 
2011; 28(6):705-714. 3123706.  
52. Stonehouse A, Walsh B, Cuddihy R. Exenatide once-weekly clinical development: safety and efficacy 
across a range of background therapies. Diabetes Technol Ther 2011; 13(10):1063-1069. 3303092.  
53. Gerich J. DPP-4 inhibitors: what may be the clinical differentiators? Diabetes Res Clin Pract 2010; 
90(2):131-140.  
54. Madsbad S. Exenatide and liraglutide: different approaches to develop GLP-1 receptor agonists 
(incretin mimetics)--preclinical and clinical results. Best Pract Res Clin Endocrinol Metab 2009; 23(4):463-
477.  
55. Houlden R, Ross S, Harris S, Yale JF, Sauriol L, Gerstein HC. Treatment satisfaction and quality of life 
using an early insulinization strategy with insulin glargine compared to an adjusted oral therapy in the 
management of Type 2 diabetes: the Canadian INSIGHT Study. Diabetes Res Clin Pract 2007; 78(2):254-
258.  
56. Nicolucci A, Cucinotta D, Squatrito S, Lapolla A, Musacchio N, Leotta S, et al. Clinical and socio-
economic correlates of quality of life and treatment satisfaction in patients with type 2 diabetes. Nutr 
Metab Cardiovasc Dis 2009; 19(1):45-53.  
57. Pratley R, Nauck M, Bailey T, Montanya E, Cuddihy R, Filetti S, et al. One year of liraglutide treatment 
offers sustained and more effective glycaemic control and weight reduction compared with sitagliptin, 
both in combination with metformin, in patients with type 2 diabetes: a randomised, parallel-group, 
open-label trial. Int J Clin Pract 2011; 65(4):397-407. 3085127.  
58. Best JH, Rubin RR, Peyrot M, Li Y, Yan P, Malloy J, et al. Weight-related quality of life, health utility, 
psychological well-being, and satisfaction with exenatide once weekly compared with sitagliptin or 
pioglitazone after 26 weeks of treatment. Diabetes Care 2011; 34(2):314-319. 3024340.  
59. Davies M, Pratley R, Hammer M, Thomsen AB, Cuddihy R. Liraglutide improves treatment satisfaction 
in people with Type 2 diabetes compared with sitagliptin, each as an add on to metformin. Diabet Med 
2011; 28(3):333-337.  
60. Pratley RE, Nauck MA, Bailey T, Montanya E, Filetti S, Garber AJ, et al. Efficacy and safety of switching 
from the DPP-4 inhibitor sitagliptin to the human GLP-1 analog liraglutide after 52 weeks in metformin-
treated patients with type 2 diabetes: a randomized, open-label trial. Diabetes Care 2012; 35(10):1986-
1993. 3447855.  
61. Flint A, Raben A, Ersboll AK, Holst JJ, Astrup A. The effect of physiological levels of glucagon-like 
peptide-1 on appetite, gastric emptying, energy and substrate metabolism in obesity. Int J Obes Relat 
Metab Disord 2001; 25(6):781-792.  
62. van Bloemendaal L, Ten Kulve JS, la Fleur SE, Ijzerman RG, Diamant M. Effects of glucagon-like peptide 
1 on appetite and body weight: focus on the CNS. J Endocrinol 2014; 221(1):T1-16.  

McComsey/Eckard GLP1RA-HIV-LH 
Version 10.0 
Protocol  
3/20/2024 
53 
 
63. Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and suppresses energy 
intake in humans. J Clin Invest 1998; 101(3):515-520. 508592.  
64. Verdich C, Flint A, Gutzwiller JP, Naslund E, Beglinger C, Hellstrom PM, et al. A meta-analysis of the 
effect of glucagon-like peptide-1 (7-36) amide on ad libitum energy intake in humans. J Clin Endocrinol 
Metab 2001; 86(9):4382-4389.  
65. Gutzwiller JP, Drewe J, Goke B, Schmidt H, Rohrer B, Lareida J, et al. Glucagon-like peptide-1 promotes 
satiety and reduces food intake in patients with diabetes mellitus type 2. Am J Physiol 1999; 276(5 Pt 
2):R1541-1544.  
66. Flint A, Kapitza C, Hindsberger C, Zdravkovic M. The once-daily human glucagon-like peptide-1 (GLP-
1) analog liraglutide improves postprandial glucose levels in type 2 diabetes patients. Adv Ther 2011; 
28(3):213-226.  
67. Shalev A, Holst JJ, Keller U. Effects of glucagon-like peptide 1 (7-36 amide) on whole-body protein 
metabolism in healthy man. Eur J Clin Invest 1997; 27(1):10-16.  
68. Kim Chung le T, Hosaka T, Yoshida M, Harada N, Sakaue H, Sakai T, et al. Exendin-4, a GLP-1 receptor 
agonist, directly induces adiponectin expression through protein kinase A pathway and prevents 
inflammatory adipokine expression. Biochem Biophys Res Commun 2009; 390(3):613-618.  
69. Ohki T, Isogawa A, Iwamoto M, Ohsugi M, Yoshida H, Toda N, et al. The effectiveness of liraglutide in 
nonalcoholic fatty liver disease patients with type 2 diabetes mellitus compared to sitagliptin and 
pioglitazone. ScientificWorldJournal 2012; 2012:496453. 3425807.  
70. Vendrell J, El Bekay R, Peral B, Garcia-Fuentes E, Megia A, Macias-Gonzalez M, et al. Study of the 
potential association of adipose tissue GLP-1 receptor with obesity and insulin resistance. Endocrinology 
2011; 152(11):4072-4079.  
71. Cantini G, Di Franco A, Samavat J, Forti G, Mannucci E, Luconi M. Effect of liraglutide on proliferation 
and differentiation of human adipose stem cells. Mol Cell Endocrinol 2015; 402:43-50.  
72. Bunck MC, Diamant M, Eliasson B, Corner A, Shaginian RM, Heine RJ, et al. Exenatide affects 
circulating cardiovascular risk biomarkers independently of changes in body composition. Diabetes Care 
2010; 33(8):1734-1737. 2909051.  
73. Yang M, Liu R, Li S, Luo Y, Zhang Y, Zhang L, et al. Zinc-alpha2-glycoprotein is associated with insulin 
resistance in humans and is regulated by hyperglycemia, hyperinsulinemia, or liraglutide 
administration: cross-sectional and interventional studies in normal subjects, insulin-resistant subjects, 
and subjects with newly diagnosed diabetes. Diabetes Care 2013; 36(5):1074-1082. 3631846.  
74. Calvani M, Scarfone A, Granato L, Mora EV, Nanni G, Castagneto M, et al. Restoration of adiponectin 
pulsatility in severely obese subjects after weight loss. Diabetes 2004; 53(4):939-947.  
75. Diaz-Soto G, de Luis DA, Conde-Vicente R, Izaola-Jauregui O, Ramos C, Romero E. Beneficial effects of 
liraglutide on adipocytokines, insulin sensitivity parameters and cardiovascular risk biomarkers in 
patients with Type 2 diabetes: a prospective study. Diabetes Res Clin Pract 2014; 104(1):92-96.  
76. Kim M, Platt MJ, Shibasaki T, Quaggin SE, Backx PH, Seino S, et al. GLP-1 receptor activation and Epac2 
link atrial natriuretic peptide secretion to control of blood pressure. Nat Med 2013; 19(5):567-575.  
77. Sengenes C, Berlan M, De Glisezinski I, Lafontan M, Galitzky J. Natriuretic peptides: a new lipolytic 
pathway in human adipocytes. FASEB J 2000; 14(10):1345-1351.  
78. Moro C, Pillard F, de Glisezinski I, Klimcakova E, Crampes F, Thalamas C, et al. Exercise-induced lipid 
mobilization in subcutaneous adipose tissue is mainly related to natriuretic peptides in overweight 
men. Am J Physiol Endocrinol Metab 2008; 295(2):E505-513.  
79. Birkenfeld AL, Budziarek P, Boschmann M, Moro C, Adams F, Franke G, et al. Atrial natriuretic peptide 
induces postprandial lipid oxidation in humans. Diabetes 2008; 57(12):3199-3204. 2584124.  

McComsey/Eckard GLP1RA-HIV-LH 
Version 10.0 
Protocol  
3/20/2024 
54 
 
80. Bordicchia M, Liu D, Amri EZ, Ailhaud G, Dessi-Fulgheri P, Zhang C, et al. Cardiac natriuretic peptides 
act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J Clin 
Invest 2012; 122(3):1022-1036. 3287224.  
81. Chen-Tournoux A, Khan AM, Baggish AL, Castro VM, Semigran MJ, McCabe EL, et al. Effect of weight 
loss after weight loss surgery on plasma N-terminal pro-B-type natriuretic peptide levels. Am J Cardiol 
2010; 106(10):1450-1455. 3170817.  
82. Chainani-Wu N, Weidner G, Purnell DM, Frenda S, Merritt-Worden T, Kemp C, et al. Relation of B-type 
natriuretic peptide levels to body mass index after comprehensive lifestyle changes. Am J Cardiol 2010; 
105(11):1570-1576.  
83. Lee YS, Park MS, Choung JS, Kim SS, Oh HH, Choi CS, et al. Glucagon-like peptide-1 inhibits adipose 
tissue macrophage infiltration and inflammation in an obese mouse model of diabetes. Diabetologia 
2012; 55(9):2456-2468.  
84. Chaudhuri A, Ghanim H, Vora M, Sia CL, Korzeniewski K, Dhindsa S, et al. Exenatide exerts a potent 
antiinflammatory effect. J Clin Endocrinol Metab 2012; 97(1):198-207. 3251936.  
85. Horton E, Cohen A, Gibson H, Lamparello B, Herzlinger S, McFarland L. Effects of exenatide vs insulin 
glargine on cardiovascular risk factors in subjects with type 2 diabetes. Diabetologia 2009; 52:S298-S299.  
86. Doggrell SA. Sgemaglutide in type 2 diabetes - is it the best glucagon-like peptide 1 receptor agonist 
(GLP-1R agonist)? Expert Opin Drug Metab Toxicol 2018; 14(3):371-377.  
87. Fujishima Y, Maeda N, Inoue K, Kashine S, Nishizawa H, Hirata A, et al. Efficacy of liraglutide, a 
glucagon-like peptide-1 (GLP-1) analogue, on body weight, eating behavior, and glycemic control, in 
Japanese obese type 2 diabetes. Cardiovasc Diabetol 2012; 11:107. 3459720.  
88. Astrup A, Carraro R, Finer N, Harper A, Kunesova M, Lean ME, et al. Safety, tolerability and sustained 
weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond) 2012; 
36(6):843-854. 3374073.  
89. Hattori Y, Jojima T, Tomizawa A, Satoh H, Hattori S, Kasai K, et al. A glucagon-like peptide-1 (GLP-1) 
analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in 
endothelial cells. Diabetologia 2010; 53(10):2256-2263.  
90. Irace C, De Luca S, Shehaj E, Carallo C, Loprete A, Scavelli F, et al. Exenatide improves endothelial 
function assessed by flow mediated dilation technique in subjects with type 2 diabetes: results from an 
observational research. Diab Vasc Dis Res 2013; 10(1):72-77.  
91. Nystrom T, Gutniak MK, Zhang Q, Zhang F, Holst JJ, Ahren B, et al. Effects of glucagon-like peptide-1 
on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol 
Endocrinol Metab 2004; 287(6):E1209-1215.  
92. Tounian P, Aggoun Y, Dubern B, Varille V, Guy-Grand B, Sidi D, et al. Presence of increased stiffness 
of the common carotid artery and endothelial dysfunction in severely obese children: a prospective 
study. Lancet 2001; 358(9291):1400-1404.  
93. Duffy SJ, Keaney JF, Jr., Holbrook M, Gokce N, Swerdloff PL, Frei B, et al. Short- and long-term black 
tea consumption reverses endothelial dysfunction in patients with coronary artery disease. Circulation 
2001; 104(2):151-156.  
94. Kim W, Jeong MH, Cho SH, Yun JH, Chae HJ, Ahn YK, et al. Effect of green tea consumption on 
endothelial function and circulating endothelial progenitor cells in chronic smokers. Circ J 2006; 
70(8):1052-1057.  
95. Zhu Y, Xia M, Yang Y, Liu F, Li Z, Hao Y, et al. Purified anthocyanin supplementation improves 
endothelial function via NO-cGMP activation in hypercholesterolemic individuals. Clin Chem 2011; 
57(11):1524-1533.  

McComsey/Eckard GLP1RA-HIV-LH 
Version 10.0 
Protocol  
3/20/2024 
55 
 
96. Dong Y, Stallmann-Jorgensen IS, Pollock NK, Harris RA, Keeton D, Huang Y, et al. A 16-week 
randomized clinical trial of 2000 international units daily vitamin D3 supplementation in black youth: 
25-hydroxyvitamin D, adiposity, and arterial stiffness. J Clin Endocrinol Metab 2010; 95(10):4584-4591.  
97. Mitchell GF, Hwang SJ, Vasan RS, Larson MG, Pencina MJ, Hamburg NM, et al. Arterial stiffness and 
cardiovascular events: the Framingham Heart Study. Circulation 2010; 121(4):505-511. 2836717.  
98. Nurnberger J, Keflioglu-Scheiber A, Opazo Saez AM, Wenzel RR, Philipp T, Schafers RF. Augmentation 
index is associated with cardiovascular risk. J Hypertens 2002; 20(12):2407-2414.  
99. Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, et al. Prognostic value of 
coronary vascular endothelial dysfunction. Circulation 2002; 106(6):653-658.  
100. Mano T, Masuyama T, Yamamoto K, Naito J, Kondo H, Nagano R, et al. Endothelial dysfunction in 
the early stage of atherosclerosis precedes appearance of intimal lesions assessable with intravascular 
ultrasound. Am Heart J 1996; 131(2):231-238.  
101. Muscelli E, Mari A, Casolaro A, Camastra S, Seghieri G, Gastaldelli A, et al. Separate impact of obesity 
and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients. Diabetes 
2008; 57(5):1340-1348.  
102. Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-
dependent) diabetes. Diabetologia 1986; 29(1):46-52.  
103. Alssema M, Rijkelijkhuizen JM, Holst JJ, Teerlink T, Scheffer PG, Eekhoff EM, et al. Preserved GLP-1 
and exaggerated GIP secretion in type 2 diabetes and relationships with triglycerides and ALT. Eur J 
Endocrinol 2013; 169(4):421-430.  
104. Vollmer K, Holst JJ, Baller B, Ellrichmann M, Nauck MA, Schmidt WE, et al. Predictors of incretin 
concentrations in subjects with normal, impaired, and diabetic glucose tolerance. Diabetes 2008; 
57(3):678-687.  
105. Nauck MA, Vardarli I, Deacon CF, Holst JJ, Meier JJ. Secretion of glucagon-like peptide-1 (GLP-1) in 
type 2 diabetes: what is up, what is down? Diabetologia 2011; 54(1):10-18.  
106. Sharkey KA, Sutherland LR, Davison JS, Zwiers H, Gill MJ, Church DL. Peptides in the gastrointestinal 
tract in human immunodeficiency virus infection. The GI/HIV Study Group of the University of Calgary. 
Gastroenterology 1992; 103(1):18-28.  
107. Schmitz H, Fromm M, Bentzel CJ, Scholz P, Detjen K, Mankertz J, et al. Tumor necrosis factor-alpha 
(TNFalpha) regulates the epithelial barrier in the human intestinal cell line HT-29/B6. J Cell Sci 1999; 112 
( Pt 1):137-146.  
108. Wensveen FM, Valentic S, Sestan M, Turk Wensveen T, Polic B. The "Big Bang" in obese fat: Events 
initiating obesity-induced adipose tissue inflammation. Eur J Immunol 2015; 45(9):2446-2456.  
109. Li X, Watanabe K, Kimura I. Gut Microbiota Dysbiosis Drives and Implies Novel Therapeutic 
Strategies for Diabetes Mellitus and Related Metabolic Diseases. Front Immunol 2017; 8:1882. 
PMC5742320.  
110. Bouter KE, van Raalte DH, Groen AK, Nieuwdorp M. Role of the Gut Microbiome in the Pathogenesis 
of Obesity and Obesity-Related Metabolic Dysfunction. Gastroenterology 2017; 152(7):1671-1678.  
111. Lackner AA, Mohan M, Veazey RS. The gastrointestinal tract and AIDS pathogenesis. 
Gastroenterology 2009; 136(6):1965-1978. PMC3755960.  
112. Kelesidis T, Kendall MA, Yang OO, Hodis HN, Currier JS. Biomarkers of microbial translocation and 
macrophage activation: association with progression of subclinical atherosclerosis in HIV-1 infection. J 
Infect Dis 2012; 206(10):1558-1567. PMC3475633.  
113. Longenecker CT, Jiang Y, Orringer CE, Gilkeson RC, Debanne S, Funderburg NT, et al. Soluble CD14 is 
independently associated with coronary calcification and extent of subclinical vascular disease in 
treated HIV infection. AIDS 2014; 28(7):969-977. 4097603.  

McComsey/Eckard GLP1RA-HIV-LH 
Version 10.0 
Protocol  
3/20/2024 
56 
 
114. McComsey G, Kitch D, Sax PE, Tebas P, Tierney C, Jahed N, et al. Peripheral and central fat Changes 
in Subjects Randomized to Abacavir/Lamivudine or Tenofovir/Emtricitabine with Atazanavir/Ritonavir 
or Efavirenz: ACTG study A5224s. CID 2011.  
115. Fitzmaurice G, Laird NM, Ware J. Applied Longitudinal Analysis. 2nd edition ed: Wiley Interscience; 
2011. 
116. Benjamini Y, Hochberg Y. Journal of the Royal Statistical Society, Series B 57 1995. 
117. Wasserstein R, Lazar N. The ASA's statement on p-values: context, process, and purpose. The 
American Statistician 2016; 70(2):129-133.  
118. Sinha SK, Sattar A. Analysis of incomplete longitudinal data with informative drop-outs and outliers. 
Canadian Journals of Statistics 2014; 42(4):670-695.  
119. Frison L, Pocock J. Repeated measures in clinical trials: Analysis using mean summary statistics and 
its implications for design. . 1992. 
120. Stat Statistical Software Release 12. In. College Station, TX: StatCorp LP; 2011. 
121. Tien PC, Benson C, Zolopa AR, Sidney S, Osmond D, Grunfeld C. The study of fat redistribution and 
metabolic change in HIV infection (FRAM): methods, design, and sample characteristics. Am J Epidemiol 
2006; 163(9):860-869. 3170407.  
122. McComsey GA, Kendall MA, Tebas P, Swindells S, Hogg E, Alston-Smith B, et al. Alendronate with 
calcium and vitamin D supplementation is safe and effective for the treatment of decreased bone 
mineral density in HIV. AIDS 2007; 21(18):2473-2482.  
123. McComsey GA, Walker UA, Budhathoki CB, Su Z, Currier JS, Kosmiski L, et al. Uridine 
supplementation in the treatment of HIV lipoatrophy: results of ACTG 5229. AIDS 2010; 24(16):2507-
2515. 2956768.  
124. McComsey GA, O'Riordan M, Choi J, Libutti D, Rowe D, Storer N, et al. Mitochondrial function, 
inflammation, fat and bone in HIV lipoatrophy: randomized study of uridine supplementation or switch 
to tenofovir. Antivir Ther 2012; 17(2):347-353. 3302940.  
125. Weir JB. New methods for calculating metabolic rate with special reference to protein metabolism. 
J Physiol 1949; 109(1-2):1-9. 1392602.  
126. Mittelsteadt AL, Hileman CO, Harris SR, Payne KM, Gripshover BM, McComsey GA. Effects of HIV and 
antiretroviral therapy on resting energy expenditure in adult HIV-infected women-a matched, 
prospective, cross-sectional study. J Acad Nutr Diet 2013; 113(8):1037-1043.  
127. Dirajlal-Fargo S, Kinley B, Jiang Y, Longenecker CT, Hileman CO, Debanne S, et al. Statin therapy 
decreases N-terminal pro-B-type natriuretic peptide in HIV: randomized placebo-controlled trial. AIDS 
2015; 29(3):313-321.  
128. Longenecker CT, Dunn W, Jiang Y, Debanne SM, McComsey GA. Adipokines and vascular health in 
treated HIV infection: an obesity paradox? AIDS 2013; 27(8):1353-1356. 4140858.  
129. Lee CJ, Brown T, Magnuson TH, Egan JM, Carlson O, Elahi D. Hormonal response to a mixed-meal 
challenge after reversal of gastric bypass for hypoglycemia. J Clin Endocrinol Metab 2013; 98(7):E1208-
1212. PMC5393460.  
130. Chia CW, Carlson OD, Kim W, Shin YK, Charles CP, Kim HS, et al. Exogenous glucose-dependent 
insulinotropic polypeptide worsens post prandial hyperglycemia in type 2 diabetes. Diabetes 2009; 
58(6):1342-1349. PMC2682676.  
131. Getty-Kaushik L, Song DH, Boylan MO, Corkey BE, Wolfe MM. Glucose-dependent insulinotropic 
polypeptide modulates adipocyte lipolysis and reesterification. Obesity (Silver Spring) 2006; 14(7):1124-
1131.  
132. Yip RG, Wolfe MM. GIP biology and fat metabolism. Life Sci 2000; 66(2):91-103.  

McComsey/Eckard GLP1RA-HIV-LH 
Version 10.0 
Protocol  
3/20/2024 
57 
 
133. Varol C, Zvibel I, Spektor L, Mantelmacher FD, Vugman M, Thurm T, et al. Long-acting glucose-
dependent insulinotropic polypeptide ameliorates obesity-induced adipose tissue inflammation. J 
Immunol 2014; 193(8):4002-4009.  
134. Burdo TH, Lo J, Abbara S, Wei J, DeLelys ME, Preffer F, et al. Soluble CD163, a novel marker of 
activated macrophages, is elevated and associated with noncalcified coronary plaque in HIV-infected 
patients. J Infect Dis 2011; 204(8):1227-1236. PMC3203384.  
135. Subramanian S, Tawakol A, Burdo TH, Abbara S, Wei J, Vijayakumar J, et al. Arterial inflammation in 
patients with HIV. JAMA 2012; 308(4):379-386. PMC3724172.  
136. Hileman CO, Labbato DE, Storer NJ, Tangpricha V, McComsey GA. Is bone loss linked to chronic 
inflammation in antiretroviral-naive HIV-infected adults? A 48-week matched cohort study. AIDS 2014; 
28(12):1759-1767.  
137. Beck J, Ferrucci L, Sun K, Fried LP, Varadhan R, Walston J, et al. Circulating oxidized low-density 
lipoproteins are associated with overweight, obesity, and low serum carotenoids in older community-
dwelling women. Nutrition 2008; 24(10):964-968. 2656364.  
138. Semba RD, Ferrucci L, Sun K, Walston J, Varadhan R, Guralnik JM, et al. Oxidative stress is associated 
with greater mortality in older women living in the community. J Am Geriatr Soc 2007; 55(9):1421-1425. 
2645668.  
139. Erlandson K, Jiang Y, debanne S, McComsey G. Rosuvastatin Worsens Insulin Resistance in HIV-
Infected Adults on Antiretroviral Therapy. Clinical Infectious Disease 2015.  
140. Muniyappa R, Lee S, Chen H, Quon MJ. Current approaches for assessing insulin sensitivity and 
resistance in vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab 2008; 
294(1):E15-26.  
141. Pelsers MM, Namiot Z, Kisielewski W, Namiot A, Januszkiewicz M, Hermens WT, et al. Intestinal-type 
and liver-type fatty acid-binding protein in the intestine. Tissue distribution and clinical utility. Clin 
Biochem 2003; 36(7):529-535.  
142. Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to 
inflammation, autoimmunity, and cancer. Physiol Rev 2011; 91(1):151-175.  
143. Pacifico L, Bonci E, Marandola L, Romaggioli S, Bascetta S, Chiesa C. Increased circulating zonulin in 
children with biopsy-proven nonalcoholic fatty liver disease. World J Gastroenterol 2014; 20(45):17107-
17114. 4258579.  
144. Zhang D, Zhang L, Yue F, Zheng Y, Russell R. Serum zonulin is elevated in women with polycystic 
ovary syndrome and correlates with insulin resistance and severity of anovulation. Eur J Endocrinol 
2015; 172(1):29-36.  
145. Hunt PW, Sinclair E, Rodriguez B, Shive C, Clagett B, Funderburg N, et al. Gut epithelial barrier 
dysfunction and innate immune activation predict mortality in treated HIV infection. J Infect Dis 2014; 
210(8):1228-1238. 4192038.  
146. Salvi P, Lio G, Labat C, Ricci E, Pannier B, Benetos A. Validation of a new non-invasive portable 
tonometer for determining arterial pressure wave and pulse wave velocity: the PulsePen device. J 
Hypertens 2004; 22(12):2285-2293.  
147. Rouxinol-Dias A, Araujo S, Silva JA, Barbosa L, Polonia J. Association between ambulatory blood 
pressure values and central aortic pressure in a large population of normotensive and hypertensive 
patients. Blood Press Monit 2018; 23(1):24-32.  
148. Eckard AR, Raggi P, Ruff JH, O'Riordan MA, Rosebush JC, Labbato D, et al. Arterial stiffness in HIV-
infected youth and associations with HIV-related variables. Virulence 2017:1-9.  
149. Takase B, Uehata A, Akima T, Nagai T, Nishioka T, Hamabe A, et al. Endothelium-dependent flow-
mediated vasodilation in coronary and brachial arteries in suspected coronary artery disease. Am J 
Cardiol 1998; 82(12):1535-1539, A1537-1538.  

McComsey/Eckard GLP1RA-HIV-LH 
Version 10.0 
Protocol  
3/20/2024 
58 
 
150. Malm-Erjefalt M, Bjornsdottir I, Vanggaard J, Helleberg H, Larsen U, Oosterhuis B, et al. Metabolism 
and excretion of the once-daily human glucagon-like peptide-1 analog liraglutide in healthy male 
subjects and its in vitro degradation by dipeptidyl peptidase IV and neutral endopeptidase. Drug Metab 
Dispos 2010; 38(11):1944-1953.