Effects of Semaglutide in HIV-Associated Lipohypertrophy

Phase 2Active Not RecruitingNCT04019197

Case Western Reserve University108 enrolled

Overview

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.

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

108

Conditions

HIV/AIDS Lipohypertrophy Obesity

Interventions

Semaglutide Injectable ProductDRUG

semaglutide subcutaneous injection

PlaceboDRUG

placebo injection

Eligibility

Sex: ALLMin age: 18 YearsHealthy volunteers:

Medical Language ↔ Plain English

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.

Locations (2)

Case Western Reserve University

Cleveland, Ohio, United States

Medical University of South Carolina

Charleston, South Carolina, United States

Outcomes

Primary Outcomes

Effects of Semaglutide on Quantity of Abdominal Fat (Total, Subcutaneous, Visceral) at Week 32 Compared to Baseline

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.

Time frame: 32 weeks

Effects of Semaglutide on Quantity of Fat (Total Body Fat, Limb Fat, Trunk Fat) at Week 32 Compared to Baseline

Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on the amount of body fat (total body fat, total limb fat, total trunk fat) as measured in mass via whole-body DXA scan.

Time frame: 32 weeks

Effects of Semaglutide on Quantity of Ectopic Fat (Total Pericardial Fat) at Week 32 Compared to Baseline

Effects of semaglutide will be investigated, including a comparison of changes overtime between participants receiving semaglutide vs. placebo, in total pericardial fat as measured by chest CT scan.

Time frame: 32 weeks

Secondary Outcomes

Effects of Semaglutide on Liver Fat at Week 32 Compared to Baseline

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. (increased density = less fat)

Time frame: 32 weeks

Effects of Semaglutide on Quantity of Lean Body Mass at Week 32 Compared to Baseline

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.

Data from ClinicalTrials.gov

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Time frame: 32 weeks

Effects of Semaglutide on Quantity of Total Right Psoas Muscle at Week 32 Compared to Baseline

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.

Time frame: 32 weeks

Effects of Semaglutide on Quality of Abdominal Fat (Total, Subcutaneous, Visceral) at Week 32 Compared to Baseline

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. (less negative = higher quality)

Time frame: 32 weeks

Effects of Semaglutide on Quality of Pericardial Fat at Week 32 Compared to Baseline

Effects of semaglutide will be investigated, including a comparison of changes overtime between participants receiving semaglutide vs. placebo, on the quality of total pericardial fat as measured by density via CT scan. (less negative = higher quality)

Time frame: 32 weeks

Effects of Semaglutide on Quality of Total Right Psoas Muscle at Week 32 Compared to Baseline

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.

Time frame: 32 weeks

Effects of Semaglutide on Anthropometric Measurements (Weight) at Week 32 Compared to Baseline

Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on anthropometric measurements.

Time frame: 32 weeks

Effects of Semaglutide on Anthropometric Measurements (Body Mass Index) at Week 32 Compared to Baseline

Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on anthropometric measurements.

Time frame: 32 weeks

Effects of Semaglutide on Anthropometric Measurements (Waist Circumference) at Week 32 Compared to Baseline

Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on anthropometric measurements.

Time frame: 32 weeks

Effects of Semaglutide on Anthropometric Measurements (Waist-to-hip Ratio) at Week 32 Compared to Baseline

Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on anthropometric measurements.

Time frame: 32 weeks

Effects of Semaglutide on Glucose Metabolism at Week 32 Compared to Baseline - Fasting Glucose

Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on glucose metabolism by assessing oral glucose tolerance, fasting glucose levels, and HgbA1C.

Time frame: 32 weeks

Effects of Semaglutide on Glucose Metabolism at Week 32 Compared to Baseline - 2-h OGTT Glucose

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.

Time frame: 32 weeks

Effects of Semaglutide on Glucose Metabolism (HgA1C%) at Week 32 Compared to Baseline

Time frame: 32 weeks

Effects of Semaglutide on Insulin Sensitivity/Resistance (Insulin Levels) at Week 32 Compared to Baseline

Time frame: 32 weeks

Effects of Semaglutide on Insulin Sensitivity/Resistance (HOMA-IR) at Week 32 Compared to Baseline

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 and HOMA-IR, calculated based on insulin levels and glucose levels with the formula (Fasting insulin, uIU/mL)\*(Fasting glucose, mg/dL) / 405). Reference levels for HOMA-IR insulin resistance range from 0.5 - 2.9 with higher values suggesting higher insulin resistance.

Time frame: 32 weeks

Effects of Semaglutide on Lipoprotein Profiles at Week 32 Compared to Baseline

Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on lipoprotein profiles.

Time frame: 32 weeks

Effects of Semaglutide on Vital Signs (Heart Rate) at 32 Weeks Compared to Baseline

Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on vital signs.

Time frame: 32 weeks

Effects of Semaglutide on Vital Signs (Blood Pressure) at 32 Weeks Compared to Baseline

Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on vital signs.

Time frame: 32 weeks

Effects of Semaglutide on Overall Cardiovascular Disease (CVD) Risk at Week 32 Compared to Baseline

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. 10-year atherosclerotic cardiovascular disease risk was estimated using the American College of Cardiology's atherosclerotic cardiovascular disease risk estimator plus (https://tools.acc.org/ascvd-risk-estimator-plus/#!/calculate/estimate/). 10-year risk for ASCVD is categorized as: Low-risk (\<5%), Borderline risk (5% to 7.4%), Intermediate risk (7.5% to 19.9%), High risk (≥20%); minimum to maximum values of 0-100% are required to interpret the median 10-year atherosclerotic cardiovascular disease risk.

Time frame: 32 weeks

Effects of Semaglutide on Dietary Intake at Week 32 Compared to Baseline

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.

Time frame: 32 weeks

Effects of Semaglutide on Physical Activity at Week 32 Compared to Baseline

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 \[International Physical Activity Questionnaire Short Version (physical activity across the previous 7 days)\]

Time frame: 32 weeks

Safety Analyses

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.

Time frame: 32 weeks

Effects of Semaglutide on Systemic Inflammation and Soluble Markers of Immune Activation (sTNFR-I, sTNFR-II, sCD14, sCD163, sVCAM-1, sICAM-1) at Week 32 Compared to Baseline

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.

Time frame: 32 weeks

Effects of Semaglutide on Systemic Inflammation and Soluble Markers of Immune Activation (D-dimer, hsCRP) at Week 32 Compared to Baseline

Time frame: 32 weeks

Effects of Semaglutide on Systemic Inflammation and Soluble Markers of Immune Activation (IL-6) at Week 32 Compared to Baseline

Time frame: 32 weeks

Effects of Semaglutide on Systemic Immune Activation (Cellular Markers) at Week 32 Compared to Baseline

Effects of semaglutide on cellular markers of inflammation and immune activation markers will be investigated to assess overall level of systemic immune activation, including a comparison of changes over time between participants receiving semaglutide vs. placebo. Cellular markers of immune activation were measured on cryopreserved PBMCs by flow cytometry. Monocyte subsets were identified based on CD14 and CD16 expression, including CD14+ CD16+ (inflammatory) and CD14dim CD16+ (patrolling) monocytes; activated CD4+ and CD8+ lymphocytes were identified as those expressing both CD38 and human leukocyte antigen (HLA)-DR; senescence/exhaustion was measured among T cells based on expression of CD28 and CD57 (CD28-CD57+) and on positive expression of PD-1. Each individual immune activation marker was quantified as the % of the total population of that particular cellular subset.

Time frame: 32 weeks

Sustainability of Effects of Semaglutide on Quantity of Fat (Total Body Fat, Limb Fat, Trunk Fat)

Time frame: 56 weeks

Sustainability of Effects of Semaglutide on Quantity of Pericardial Fat

Time frame: 56 weeks

Sustainability of Effects of Semaglutide on Liver Fat

Time frame: 56 weeks

Sustainability of Effects of Semaglutide on Quantity of Lean Body Mass

Time frame: 56 weeks

Sustainability of Effects of Semaglutide on Quantity of Total Right Psoas Muscle

Time frame: 56 weeks

Sustainability of Effects of Semaglutide on Quality of Abdominal Fat (Total, Subcutaneous, Visceral)

Time frame: 56 weeks

Sustainability of Effects of Semaglutide on Quality of Pericardial Fat

Time frame: 56 weeks

Sustainability of Effects of Semaglutide on Quality of Total Right Psoas Muscle

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.

Time frame: 56 weeks

Sustainability of Effects of Semaglutide on Anthropometric Measurements (Weight, Waist Circumference, Waist-to-hip Ratio)

Time frame: 56 weeks

Sustainability of Effects of Semaglutide on Glucose Metabolism

Time frame: 56 weeks

Sustainability of Effects of Semaglutide on Lipoprotein Profiles

Time frame: 56 weeks

Sustainability of Effects of Semaglutide on Systemic Inflammation

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.

Time frame: 56 weeks

Sustainability of Effects of Semaglutide on Systemic Immune Activation

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.

Time frame: 56 weeks

Sustainability of Effects of Semaglutide on Insulin Sensitivity/Resistance

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.

Time frame: 56 weeks

Sustainability of Effects of Semaglutide on Gut Hormones

Time frame: 56 weeks

Sustainability of Effects of Semaglutide on Gut Integrity

Time frame: 56 weeks

Sustainability of Effects of Semaglutide on Resting Energy Expenditure

Time frame: 56 weeks

Sustainability of Effects of Semaglutide on Pulse Wave Velocity

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.

Time frame: 56 weeks

Sustainability of Effects of Semaglutide on EndoPat

Time frame: 56 weeks

Sustainability of Effects of Semaglutide on Coronary Artery Calcium (CAC) Score

Time frame: 56 weeks