Effects of Semaglutide in HIV-Associated Lipohypertrophy

Study Overview
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Brief Summary
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This is a randomized, double-blinded, placebo-controlled trial designed to assess the effect of the GLP-1 receptor agonist, semaglutide, on visceral and ectopic fat, insulin resistance, inflammation markers, and the downstream effect of cardiovascular risk in people with HIV. The primary endpoints will be visceral and ectopic fat changes over the study period. The secondary endpoints will include changes in markers of inflammation, immune activation, gut integrity, and cardiovascular disease risk assessment.

Detailed Description
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This study is a phase IIb, randomized, double-blinded, placebo-controlled clinical trial of semaglutide in people with HIV-associated lipohypertrophy. Participants will be recruited from 2 different sites (Cleveland, OH and Charleston, SC). The duration of the study will be 56 weeks. The interventional phase will last 32 weeks, followed by a 24-week observational phase to assess the sustainability of the intervention. Participants will be randomized 1:1 to receive semaglutide by subcutaneous injection once weekly for 32 weeks (8-week dose escalation phase followed by full-dose for 24 weeks) or matching placebo. The primary objective of this clinical trial is to determine the efficacy of semaglutide in treating lipohypertrophy among non-diabetic people living with HIV 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.

Official Title
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Effects of GLP-l Receptor Agonists on Cardiometabolic Alterations in HIV-associated Lipohypertrophy

Conditions
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HIV/AIDS, Lipohypertrophy, Obesity

Intervention / Treatment
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* Drug: Semaglutide Injectable Product
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, aged ≥18 years. 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. Body mass index ≥25 kg/m2. 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. Subjective evidence of increased abdominal girth occurring after initiation of HIV treatment. HIV-1 RNA <400 copies/mL for ≥6 months. 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. Provision of signed and dated informed consent form and is capable of reading and comprehending the informed consent. Stated willingness to comply with all study procedures and availability for the duration of the study. 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. 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. 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. 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. Exclusion Criteria: 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. Any active or chronic uncontrolled inflammatory condition, infection or cancer. Women who are pregnant or breastfeeding. Women with a positive pregnancy test on enrollment or prior to study drug administration. 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. Active gastrointestinal symptom Grade >1 within the last month. 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. Inability to communicate effectively with study personnel. 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. Glomerular filtration rate <50 cc/min/1.73 m2. Hemoglobin <10 g/dL. Elevated lipase level >1.5 upper limit of normal AST AND ALT >2.5x upper limit of normal. Use of growth hormone or growth hormone-releasing hormone in the last year, or intent to start. 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. History of lactose intolerance or inability to consume milk products will be exclusionary for participation in the mixed-meal tolerance test portion of the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Participants with HIV and lipohypertrophy: semaglutide arm<br>Participants with HIV/lipohypertrophy will receive semaglutide 0.25 mg x4 weeks, then semaglutide 0.5 mg x4 weeks, then semaglutide 1.0 mg x24 weeks, then no drug x24 weeks. | Drug: Semaglutide Injectable Product<br>* semaglutide subcutaneous injection<br>* Other names: Ozempic;|
| Placebo Comparator: Participants with HIV and lipohypertrophy: placebo arm<br>Participants with HIV/Lipohypertrophy will receive placebo x32 weeks, then no placebo for 24 weeks. | Drug: Placebo<br>* placebo injection<br>* Other names: placebos;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in visceral abdominal fat | A comparison of changes over time will be made between participants receiving semaglutide vs. placebo in the amount of visceral abdominal fat as measured by abdominal CT scan. | 56 weeks | 
| Changes in subcutaneous abdominal fat | A comparison of changes over time will be made in the amount of subcutaneous abdominal fat as measured by abdominal CT scan in participants with HIV receiving semaglutide vs. placebo. | 56 weeks | 
| Changes in epicardial fat | A comparison of changes over time will be made in the amount of epicardial fat as measured by chest CT scan in participants receiving semaglutide vs. placebo. | 56 weeks | 
| Changes in amount of fat by DXA scan | A comparison of changes over time will be made between participants receiving semaglutide vs. placebo in the amount of total fat, limb fat, and trunk fat as measured by whole-body DXA. | 56 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in pulse wave velocity | A comparison of changes over time will be made between participants receiving semaglutide vs. placebo in pulse wave velocity, a measure of arterial stiffness, as a surrogate measure of cardiovascular disease risk. | 56 weeks | 
| Changes in EndoPat | A comparison of changes over time will be made between participants receiving semaglutide vs. placebo in EndoPat, a measure of endothelial function, as a surrogate measure of cardiovascular disease risk. | 56 weeks | 
| Changes in inflammation | A comparison of changes over time will be made between participants receiving semaglutide vs. placebo in pro-inflammatory markers (sCD14, sCD163, hsCRP, IL-6, sTNFR-1, sTNRF-II) to assess overall level of inflammation. | 56 weeks | 
| Changes in gut hormones | A comparison of changes over time will be made between participants receiving semaglutide vs. placebo in the gut hormones, GIP and GLP-1 levels, by means of a mixed-meal tolerance test. | 56 weeks | 
| Changes in liver fat | A comparison of changes over time will be made between participants receiving semaglutide vs. placebo in the amount of liver fat, as measured by abdominal CT scan. | 56 weeks | 
| Changes in gut integrity | A comparison of changes over time will be made between participants receiving semaglutide vs. placebo in several measures of gut integrity and microbial translocation (I-FABP, zonulin-1, LPS). | 56 weeks | 
| Changes in insulin sensitivity | A comparison of changes over time will be made between participants receiving semaglutide vs. placebo in insulin sensitivity by means of assessing HOMA-IR (calculated based on insulin levels and glucose levels). | 56 weeks | 
| Changes in glucose metabolism | A comparison of changes over time will be made between participants receiving semaglutide vs. placebo in glucose metabolism collectively by assessing oral glucose tolerance, fasting glucose levels, and HgbA1C. | 56 weeks | 
| Changes in resting energy expenditure | A comparison of changes over time will be made between participants receiving semaglutide vs. placebo in resting energy expenditure by means of indirect calorimetry. | 56 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, lipohypertrophy, semaglutide, GLP-1 receptor agonist, obesity