Early Metabolic Effects of Antiretroviral Drugs in Healthy Volunteers: A Phase 2 Randomized Study
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 120
- 试验地点
- 1
- 主要终点
- Change in 24-hour energy expenditure and 24-hour RQ from baseline to day 1 and day 8 of ARV therapy with each drug
研究概览
简要总结
Background:
People with HIV take drugs to keep the amount of virus in their body low. One type of these drugs, called integrase strand transfer inhibitors (INSTIs), can cause weight gain over time. Weight gain can cause diabetes, heart disease, and other serious issues. Researchers want to understand how INSTIs cause weight changes.
Objective:
To characterize the change in plasma metabolite profile that 4 weeks of each treatment may induce in the absence of HIV infection
Eligibility:
Healthy people aged 18 to 55.
Design:
Participants will be screened in the outpatient clinic. They will have a physical exam and blood tests. They will have a nutritional assessment and tests of their heart function.
Participants will be randomized to one of four oral treatments: Tenofovir Disoproxil Fumarate TDF, Tenovovir Alafenamide TAF/Vemlidy, Dolutegravir DTG/Tivicay, or both TAF and DTG taken together for 4 weeks.
Participants will have a Day 0 visit for the Lead-In Baseline visit for an exam and blood tests and continuous glucose monitor placement.
Participants will return in 2wks or Day 14/Wk 2 for a DEXA (dual-energy X-ray absorptiometry). DEXA is a kind of X-ray that measures body fat and bone density. Optional adiopse (fat) tissue biopsy in the abdomen, and optional microbiome specimen collections. Continuous glucose monitor changed. Oral once a day dose medication will be started with education.
Participants will return in 2wks or Day 28/Wk 4 for exam, labs, and continuous glucose monitor changed.
Participants will return in 2wks or Day 42/Wk 6 for final exam, labs, repeat DEXA scan, repeat adipose tissue biopsy, and microbiome specimen collections.
详细描述
Study Description:
Integrase strand transfer inhibitors (INSTIs) are a class of antiretroviral (ARV) drugs that are currently among first-line therapies to treat and prevent HIV. Several observational trials have shown that one side effect of this class of ARVs is involuntary weight gain. How these drugs cause weight gain is incompletely understood. In addition, one of these marketed drugs (bictegravir) is coformulated in combination with the nucleotide reverse transcriptase inhibitor (NRTI) tenofovir alafenamide (TAF), which may also independently contribute to weight gain, including when it is compared against the related prodrug tenofovir disoproxil fumarate (TDF). To better understand the effects of INSTIs and TAF on metabolism, healthy volunteer participants will be randomized 1:1:1:1 to one of four arms: the INSTI dolutegravir (DTG), TAF, DTG plus TAF, or TDF. Participants will undergo an initial screening evaluation, a 2-week treatment-free lead-in period, and then a 4-week open-label treatment phase during which they will take the assigned study drug(s). During the study, participants will be assessed for changes in metabolic pathways, metabolites, and gene expression using a multi-omic approach. They will undergo serial research sample collection, including adipose tissue biopsy and microbiome sampling, both prior to initiation and after 4 weeks of the study drug(s).
Objectives:
Primary Objective:
To characterize the change in plasma metabolite profile that 4 weeks of each treatment may induce in the absence of HIV infection.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None (Investigator)
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •INCLUSION CRITERIA:
- •In order to be eligible to participate in this study, an individual must meet all of the following criteria:
- •Aged 18 to 55 years.
- •Able to provide informed consent.
- •Willing to allow samples and data to be stored and shared for future research.
- •Agrees to use a barrier method of contraception or abstain from sexual activity starting at screening though the end of study participation.
排除标准
- •An individual who meets any of the following criteria will be excluded from participation in this study:
- •Current infection with HIV or hepatitis A, B, or C.
- •Body mass index (BMI) <18.5 kg/m^2 or >30.0 kg/m^
- •Weight change >5% in the past 6 months.
- •History of or current cardiovascular disease such as congestive heart failure, heart block, or clinically relevant abnormal ECG as determined by investigators.
- •History of or current liver disease or alanine transaminase serum level >2x upper limit of normal.
- •History of or current kidney disease or renal insufficiency, or estimated creatinine clearance <=80 mL/min (Modification of Diet in Renal Disease equation).
- •Current cancer or history of cancer within 5 years of screening, with the exception of squamous cell carcinoma or basal cell carcinoma that is localized and does not require systemic therapy.
- •History of bariatric surgery.
- •Diabetes mellitus as defined by a prior diagnosis or a hemoglobin A1c of >6.4 percent on screening labs.
- •Fasting serum glucose >126 mg/dL.
- •History of or current hypo- or hyper-thyroid or abnormal TSH, except minor deviations deemed to be of no clinical significance by the investigator.
- •History of chronic obstructive pulmonary disease.
- •Psychological conditions by self-report, such as (but not limited to) clinical depression, or bipolar disorders, which would be incompatible with safe and successful participation in this study.
- •Pregnancy or within 1 year post-partum.
- •Breastfeeding.
- •Blood pressure >140/90 mm Hg or current antihypertensive therapy.
- •Hemoglobin that is either 10 percent below the lower limit or 10 percent above the upper limit of the normal range for the Clinical Center Laboratory (acceptable ranges: females 10.08-17.27 g/dL, males 12.33-19.25 g/dL).
- •History of illicit drug, opioid, or alcohol abuse within the last 5 years; current use of illicit drugs or opioids (by history) or excessive alcohol (CAGE assessment score >=2).
- •Current use of the following prescription or over-the-counter medications and supplements:
- •Carbamazepine
- •Oxcarbazepine
- •Phenobarbital
- •Phenytoin
- •Primidone
- •Rifabutin
- •Rifapentine
- •St. John's wort (Hypericum perforatum)
- •Cation-containing antacids or laxatives
- •Sucralfate
- •Buffered medications
- •Oral calcium, iron, magnesium, or zinc supplements, including multivitamins containing these polyvalent cations
- •Dalfampridine
- •Metformin
- •Dofetilide
- •Thyroid medications
- •Corticosteroids
- •Weight loss medications, including prescription drugs (eg, semaglutide and tirzepatide) and over-the-counter diet pills
- •Use of TAF, TDF, and/or FTC for the purpose of HIV PrEP or in a research study within the past 6 months.
- •Any history of exposure to cabotegravir or lenacapavir (eg, as HIV PrEP or as a participant in a research study for these drugs).
- •Current use of prescription or nonprescriptive medications that may have interactions with study drugs or confound the study measurements as determined by the investigators.
- •History of adverse or allergic reactions to the study drugs.
- •Daily caffeine intake >500 mg (about 4 cups of coffee).
- •Current smoker or user of tobacco products.
- •A change in the participant's diet and/or exercise regimen in the past 3 months or during the timeframe of the study period that, in the opinion of the investigator, would compromise the integrity of the data.
- •High-risk sexual activity as determined by the investigators, and/or inability or unwillingness to use barrier contraception during the protocol.
- •Any other condition, medication, or dietary pattern that, in the opinion of the investigators, increases risk to the participant, prevents the participant from complying with study procedures, prevents the participant from completing the study, or interferes with the interpretation of study results.
研究组 & 干预措施
Dolutegravir
50mg one tablet orally once a day for 4 weeks, Day 14 to Day 42
干预措施: Dolutegravir (Drug)
Tenofovir Disoproxil Fumarate
300mg one tablet orally once daily for 4 weeks, Day 14 to Day 42
干预措施: Tenofovir Disoproxil Fumarate (Drug)
Dolutegravir AND Tenofovir alafenamide
50mg one tablet orally AND 25mg one tablet orally together once a day for 4 weeks, Day 14 to Day 42
干预措施: Dolutegravir (DTG) AND Tenofovir alafenamide (TAF) (Drug)
Tenofovir alafenamide
25mg one tablet orally once a day for 4 weeks, Day 14 to Day 42
干预措施: Tenofovir alafenamide (Drug)
结局指标
主要结局
Change in 24-hour energy expenditure and 24-hour RQ from baseline to day 1 and day 8 of ARV therapy with each drug
时间窗: Baseline to day 1 and Day 8 of ARV therapy for drug regimen.
To determine if TAF or DTG induce changes in 24-hour energy expenditure and 24-hour respiratory quotient (RQ)
Change in plasma metabolites from ARV initiation to the end of the 4 week period of ARV therapy with each treatment
时间窗: Day 14/Wk2 to Day 42/Wk6 of ARV therapy for each of 4 drug regimen.
To determine if TAF or DTG or TDF or DTG/TAF induce changes in plasma metabolites in the 4wks of therapy
次要结局
- Relationship between demographic data or baseline laboratory values and changes in energy expenditure or caloric intake(Throughout study)
- Relationship between pharmacokinetic parameters for TAF and DTG and changes in energy expenditure or caloric intake.(Days 10 and 38)
- Encompassing transcriptomic changes, metabolic alterations, lipidomic shifts, and proteomic variations.(Throughout study - Baseline to Day 42/Wk 6)
- Comprehensive multi-omic profile changes in plasma, PBMCs, and adipose tissue from ARV initiation to the end of the 4 week treatment period with each of four treatments(Throughout study - Baseline to Day 42/Wk 6)
- Relationship between demographic data or baseline laboratory values and multi-omic profile changes in plasma, PBMC, and adipose tissue.(Throughout study - Baseline to Day 42/Wk 6)
- Multi-omic comparisons between DTG and/or TAF versus TDF.(Throughout study - Baseline to Day 42/Wk 6)