Effects of Semaglutide in HIV-Associated Lipohypertrophy

Phase 2

Active, not recruiting

• Conditions: HIV/AIDS; Lipohypertrophy; Obesity
• Interventions: Drug: Semaglutide Injectable Product; Drug: Placebo

• Registration Number: NCT04019197
• Lead Sponsor: Case Western Reserve University

Brief Summary

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

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 1 site (Cleveland, OH). 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.

Study Timeline

• Study Start: 2019-05-16
• Study First Submitted: 2019-07-01
• Study First Submitted QC: 2019-07-11
• Study First Posted: 2019-07-15
• Primary Completion: 2023-09-30
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-20
• Last Update Posted: 2024-03-21
• Study Completion: 2025-03-31

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 108

Inclusion 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.
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.

Exclusion Criteria

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. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Participants with HIV and lipohypertrophy: semaglutide arm	Semaglutide Injectable Product	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.
Participants with HIV and lipohypertrophy: placebo arm	Placebo	Participants with HIV/Lipohypertrophy will receive placebo x32 weeks, then no placebo for 24 weeks.

Primary Outcome Measures

Name	Time	Method
Effects of semaglutide on quantity of abdominal fat (total, subcutaneous, visceral)	32 weeks	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on the amount of abdominal fat (total, subcutaneous, visceral) as measured in area via abdominal CT scan.
Effects of semaglutide on quantity of fat (total body fat, limb fat, trunk fat)	32 weeks	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on the amount of abdominal fat (total, subcutaneous, visceral) as measured in mass via whole-body DXA scan.
Effects of semaglutide on quantity of pericardial fat	32 weeks	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on the amount of pericardial fat as measured in volume by chest CT scan.

Secondary Outcome Measures

Name	Time	Method
Effects of semaglutide on anthropometric measurements (weight, waist circumference, waist-to-hip ratio)	32 weeks	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on anthropometric measurements.
Effects of semaglutide on liver fat	32 weeks	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on liver fat as measured by density via abdominal CT scan.
Effects of semaglutide on quantity of lean body mass	32 weeks	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on the amount of lean body mass as measured by whole-body DXA scan.
Effects of semaglutide on quantity of total right psoas muscle	32 weeks	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on the amount of total right psoas muscle as measured in area via CT scan.
Effects of semaglutide on quality of abdominal fat (total, subcutaneous, visceral)	32 weeks	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on the quality of abdominal fat (total, subcutaneous, visceral) as measured by density via CT scan.
Effects of semaglutide on quality of pericardial fat	32 weeks	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on the quality of pericardial fat (total, subcutaneous, visceral) as measured by density via abdominal CT scan.
Effects of semaglutide on quality of total right psoas muscle	32 weeks	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on the quality/intermuscular fat content of total right psoas muscle as measured by density via CT scan.
Effects of semaglutide on glucose metabolism	32 weeks	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on on glucose metabolism by assessing oral glucose tolerance, fasting glucose levels, and HgbA1C.
Effects of semaglutide on lipoprotein profiles	32 weeks	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on lipoprotein profiles and oxidized LDL levels.
Effects of semaglutide on systemic inflammation	32 weeks	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on soluble markers of inflammation and immune activation to assess overall level of systemic inflammation.
Effects of semaglutide on systemic immune activation	32 weeks	Effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on cellular markers of inflammation and immune activation markers to assess overall level of systemic immune activation.
Effects of semaglutide on insulin sensitivity/resistance	32 weeks	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on insulin sensitivity/insulin resistance by assessing insulin levels, HOMA-IR (calculated based on insulin levels and glucose levels), and timed insulin levels as part of a 4-hour mixed meal tolerance test.
Effects of semaglutide on gut hormones	32 weeks	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, in the gut hormones, GIP and GLP-1 levels, by means of a 4-hour mixed-meal tolerance test.
Effects of semaglutide on gut integrity	32 weeks	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, in select measures of gut integrity and microbial translocation (e.g., I-FABP, zonulin-1, LPS).
Effects of semaglutide on resting energy expenditure	32 weeks	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, in resting energy expenditure by means of indirect calorimetry.
Effects of semaglutide on pulse wave velocity	32 weeks	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, in pulse wave velocity, a measure of arterial stiffness, as a surrogate measure of cardiovascular disease risk.
Effects of semaglutide on EndoPat	32 weeks	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, in EndoPat, a measure of endothelial function, as a surrogate measure of cardiovascular disease risk.
Effects of semaglutide on coronary artery calcium (CAC) score	32 weeks	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, in coronary artery calcium (CAC) score as measured by chest CT scan.
Effects of semaglutide on overall cardiovascular disease (CVD) risk	32 weeks	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, in overall cardiovascular disease (CVD) risk.
Effects of semaglutide on bone	32 weeks	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on bone markers and total bone mineral content as measured by whole-body DXA scan.
Effects of semaglutide on dietary intake	32 weeks	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on dietary intake via comprehensive dietary intake assessments.
Effects of semaglutide on physical activity	32 weeks	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on physical activity status via comprehensive physical activity assessments.
Safety analyses	32 weeks	Safety of semaglutide in HIV will be investigated, including a comparison between participants receiving semaglutide vs. placebo, on adverse events, side effects, and related safety endpoints.
Sustainability of effects of semaglutide on quantity of abdominal fat (total, subcutaneous, visceral)	56 weeks	Sustainability of effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants who received semaglutide vs. placebo, on the amount of abdominal fat (total, subcutaneous, visceral) as measured in area via abdominal CT scan.
Sustainability of effects of semaglutide on quantity of fat (total body fat, limb fat, trunk fat)	56 weeks	Sustainability of effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants who received semaglutide vs. placebo, on the amount of total fat, limb fat, and trunk fat as measured in mass via whole-body DXA scan.
Sustainability of effects of semaglutide on quantity of pericardial fat	56 weeks	Sustainability of effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants who received semaglutide vs. placebo, on the amount of pericardial fat as measured in volume by chest CT scan.
Sustainability of effects of semaglutide on liver fat	56 weeks	Sustainability of effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants who received semaglutide vs. placebo, on liver fat as measured by density via abdominal CT scan.
Sustainability of effects of semaglutide on quantity of lean body mass	56 weeks	Sustainability of effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants who received semaglutide vs. placebo, on the amount of lean body mass as measured by whole-body DXA scan.
Sustainability of effects of semaglutide on quantity of total right psoas muscle	56 weeks	Sustainability of effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants who received semaglutide vs. placebo, on the amount of total right psoas muscle as measured in area via CT scan.
Sustainability of effects of semaglutide on quality of abdominal fat (total, subcutaneous, visceral)	56 weeks	Sustainability of effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants who received semaglutide vs. placebo, on the quality of abdominal fat (total, subcutaneous, visceral) as measured by density via CT scan.
Sustainability of effects of semaglutide on quality of pericardial fat	56 weeks	Sustainability of effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants who received semaglutide vs. placebo, on the quality of pericardial fat as measured by density via chest CT scan.
Sustainability of effects of semaglutide on quality of total right psoas muscle	56 weeks	Sustainability of effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants who received semaglutide vs. placebo, on the quality/intermuscular fat content of total right psoas muscle as measured in density via CT scan.
Sustainability of effects of semaglutide on anthropometric measurements (weight, waist circumference, waist-to-hip ratio)	56 weeks	Sustainability of effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants who received semaglutide vs. placebo, on anthropometric measurements.
Sustainability of effects of semaglutide on glucose metabolism	56 weeks	Sustainability of effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants who received semaglutide vs. placebo, on glucose metabolism by assessing oral glucose tolerance, fasting glucose levels, and HgbA1C.
Sustainability of effects of semaglutide on lipoprotein profiles	56 weeks	Sustainability of effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants who received semaglutide vs. placebo, on lipoprotein profiles and oxidized LDL levels.
Sustainability of effects of semaglutide on systemic inflammation	56 weeks	Sustainability of effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants who received semaglutide vs. placebo, on soluble markers of inflammation and immune activation markers to assess overall level of systemic inflammation.
Sustainability of effects of semaglutide on systemic immune activation	56 weeks	Sustainability of effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants who received semaglutide vs. placebo, on cellular markers of inflammation and immune activation markers to assess overall level of systemic immune activation.
Sustainability of effects of semaglutide on insulin sensitivity/resistance	56 weeks	Sustainability of effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants who received semaglutide vs. placebo, on soluble markers of inflammation and immune activation markers by assessing insulin levels, HOMA-IR (calculated based on insulin levels and glucose levels), and timed insulin levels as part of a 4-hour mixed meal tolerance test.
Sustainability of effects of semaglutide on gut hormones	56 weeks	Sustainability of effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants who received semaglutide vs. placebo, on gut hormones, GIP and GLP-1 levels, by means of a 4-hour mixed-meal tolerance test.
Sustainability of effects of semaglutide on gut integrity	56 weeks	Sustainability of effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants who received semaglutide vs. placebo, on gut integrity and microbial translocation (e.g., I-FABP, zonulin-1, LPS).
Sustainability of effects of semaglutide on resting energy expenditure	56 weeks	Sustainability of effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants who received semaglutide vs. placebo, on resting energy expenditure by means of indirect calorimetry.
Sustainability of effects of semaglutide on pulse wave velocity	56 weeks	Sustainability of effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants who received semaglutide vs. placebo, on pulse wave velocity, a measure of arterial stiffness, as a surrogate measure of cardiovascular disease risk.
Sustainability of effects of semaglutide on EndoPat	56 weeks	Sustainability of effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants who received semaglutide vs. placebo, on EndoPat, a measure of endothelial function, as a surrogate measure of cardiovascular disease risk.
Sustainability of effects of semaglutide on coronary artery calcium (CAC) score	56 weeks	Sustainability of effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants who received semaglutide vs. placebo, on coronary artery calcium (CAC) score as measured by chest CT scan.
Sustainability of effects of semaglutide on overall cardiovascular disease (CVD) risk	56 weeks	Sustainability of effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants who received semaglutide vs. placebo, on overall cardiovascular disease (CVD) risk.
Sustainability of effects of semaglutide on bone	56 weeks	Sustainability of effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants who received semaglutide vs. placebo, on bone markers and total bone mineral content as measured by whole-body DXA scan.
Sustainability of effects of semaglutide on dietary intake	56 weeks	Sustainability of effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants who received semaglutide vs. placebo, on dietary intake via comprehensive dietary intake assessments.
Sustainability of effects of semaglutide on physical activity	56 weeks	Sustainability of effects of semaglutide after treatment discontinuation will be investigated, including a comparison of changes over time between participants who received semaglutide vs. placebo, on physical activity status via comprehensive physical activity assessments.

Trial Locations

Locations (2)

Case Western Reserve University; 🇺🇸 Cleveland, Ohio, United States

Medical University of South Carolina; 🇺🇸 Charleston, South Carolina, United States