Effects of Semaglutide in HIV-Associated Lipohypertrophy

Obesity Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04019197
• Other study ID #: STUDY20190121
• Secondary ID: R01DK121619
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: May 16, 2019
• Est. completion date: March 31, 2025

Study information

• Verified date: March 2024
• Source: Case Western Reserve University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 108
• Est. completion date: March 31, 2025
• Est. primary completion date: September 30, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• HIV/AIDS
• Lipohypertrophy
• Obesity

Intervention

Drug:
• Semaglutide Injectable Product
semaglutide subcutaneous injection
• Placebo
placebo injection

Locations

Country	Name	City	State
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Case Western Reserve University	Cleveland	Ohio

Sponsors (3)

Lead Sponsor	Collaborator
Case Western Reserve University	Medical University of South Carolina, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Effects of semaglutide on adipokines and natriuretic peptides	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on adipokines and natriuretic peptides to help elucidate the potential mechanism by which GLP-1 may affect metabolic endpoints.	32 weeks
Other	Exploratory investigation of mechanisms of semaglutide effects on outcome measures	Outcome measures will be evaluated for possible mechanisms/pathways that help elucidate causal effects of semaglutide in people with HIV/HIV-associated lipohypertrophy.	32 weeks
Other	Effects of semaglutide on neurocognitive scores	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on neurocognitive scores assessed using Cognivue test.	32 weeks
Other	Effects of semaglutide on skin AGE measurements	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on skin AGE measurements via AGE Reader instrument.	32 weeks
Other	Sustainability of effects of semaglutide on natriuretic peptides	A comparison of changes over time will be made between participants receiving semaglutide vs. placebo in adipokines and natriuretic peptides to help elucidate the potential mechanism by which GLP-1 may affect metabolic endpoints.	56 weeks
Other	Sustainability of effects of semaglutide on neurocognitive scores	A comparison of changes over time will be made between participants receiving semaglutide vs. placebo in neurocognitive scores assessed using Cognivue test.	56 weeks
Other	Sustainability of effects of semaglutide on skin AGE measurements	A comparison of changes over time will be made between participants receiving semaglutide vs. placebo in skin AGE measurements via AGE Reader instrument.	56 weeks
Other	Investigation of mechanisms of semaglutide effects and sustainability of effects on outcome measures	Outcome measures will be evaluated for possible mechanisms/pathways that help elucidate causal effects of semaglutide in people with HIV.	56 weeks
Other	Changes over time in HIV-associated lipohypertrophy	All outcome measures will be assessed for changes over time among participants receiving placebo to help determine the natural course of lipohypertrophy in HIV.	56 weeks
Primary	Effects of semaglutide on quantity of abdominal fat (total, subcutaneous, visceral)	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.	32 weeks
Primary	Effects of semaglutide on quantity of fat (total body fat, limb fat, trunk fat)	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.	32 weeks
Primary	Effects of semaglutide on quantity of pericardial fat	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.	32 weeks
Secondary	Effects of semaglutide on liver fat	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.	32 weeks
Secondary	Effects of semaglutide on quantity of lean body mass	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.	32 weeks
Secondary	Effects of semaglutide on quantity of total right psoas muscle	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.	32 weeks
Secondary	Effects of semaglutide on quality of abdominal fat (total, subcutaneous, visceral)	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.	32 weeks
Secondary	Effects of semaglutide on quality of pericardial fat	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.	32 weeks
Secondary	Effects of semaglutide on quality of total right psoas muscle	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.	32 weeks
Secondary	Effects of semaglutide on anthropometric measurements (weight, waist circumference, waist-to-hip ratio)	Effects of semaglutide will be investigated, including a comparison of changes over time between participants receiving semaglutide vs. placebo, on anthropometric measurements.	32 weeks
Secondary	Effects of semaglutide on glucose metabolism	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.	32 weeks
Secondary	Effects of semaglutide on lipoprotein profiles	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.	32 weeks
Secondary	Effects of semaglutide on systemic inflammation	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.	32 weeks
Secondary	Effects of semaglutide on systemic immune activation	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.	32 weeks
Secondary	Effects of semaglutide on insulin sensitivity/resistance	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.	32 weeks
Secondary	Effects of semaglutide on gut hormones	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.	32 weeks
Secondary	Effects of semaglutide on gut integrity	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).	32 weeks
Secondary	Effects of semaglutide on resting energy expenditure	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.	32 weeks
Secondary	Effects of semaglutide on pulse wave velocity	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.	32 weeks
Secondary	Effects of semaglutide on EndoPat	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.	32 weeks
Secondary	Effects of semaglutide on coronary artery calcium (CAC) score	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.	32 weeks
Secondary	Effects of semaglutide on overall cardiovascular disease (CVD) risk	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.	32 weeks
Secondary	Effects of semaglutide on bone	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.	32 weeks
Secondary	Effects of semaglutide on dietary intake	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.	32 weeks
Secondary	Effects of semaglutide on physical activity	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.	32 weeks
Secondary	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.	32 weeks
Secondary	Sustainability of effects of semaglutide on quantity of abdominal fat (total, subcutaneous, visceral)	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.	56 weeks
Secondary	Sustainability of effects of semaglutide on quantity of fat (total body fat, limb fat, trunk fat)	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.	56 weeks
Secondary	Sustainability of effects of semaglutide on quantity of pericardial fat	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.	56 weeks
Secondary	Sustainability of effects of semaglutide on liver fat	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.	56 weeks
Secondary	Sustainability of effects of semaglutide on quantity of lean body mass	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.	56 weeks
Secondary	Sustainability of effects of semaglutide on quantity 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 amount of total right psoas muscle as measured in area via CT scan.	56 weeks
Secondary	Sustainability of effects of semaglutide on quality of abdominal fat (total, subcutaneous, visceral)	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.	56 weeks
Secondary	Sustainability of effects of semaglutide on quality of pericardial fat	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.	56 weeks
Secondary	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.	56 weeks
Secondary	Sustainability of effects of semaglutide on anthropometric measurements (weight, waist circumference, waist-to-hip ratio)	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.	56 weeks
Secondary	Sustainability of effects of semaglutide on glucose metabolism	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.	56 weeks
Secondary	Sustainability of effects of semaglutide on lipoprotein profiles	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.	56 weeks
Secondary	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.	56 weeks
Secondary	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.	56 weeks
Secondary	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.	56 weeks
Secondary	Sustainability of effects of semaglutide on gut hormones	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.	56 weeks
Secondary	Sustainability of effects of semaglutide on gut integrity	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).	56 weeks
Secondary	Sustainability of effects of semaglutide on resting energy expenditure	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.	56 weeks
Secondary	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.	56 weeks
Secondary	Sustainability of effects of semaglutide on EndoPat	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.	56 weeks
Secondary	Sustainability of effects of semaglutide on coronary artery calcium (CAC) score	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.	56 weeks
Secondary	Sustainability of effects of semaglutide on overall cardiovascular disease (CVD) risk	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.	56 weeks
Secondary	Sustainability of effects of semaglutide on bone	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.	56 weeks
Secondary	Sustainability of effects of semaglutide on dietary intake	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.	56 weeks
Secondary	Sustainability of effects of semaglutide on physical activity	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.	56 weeks