Uridine Supplementation, Mitochondrial Function, and Glucose Metabolism in HIV
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 3
- 试验地点
- 1
- 主要终点
- Change in insulin sensitivity as measured by euglycemic hyperinsulinemic clamp (with simultaneous stable isotope tracer studies)
研究概览
简要总结
The purpose of this study is to determine whether uridine supplementation will improve insulin sensitivity and overall carbohydrate metabolism in HIV-positive subjects who are currently undergoing treatment with antiretroviral regimens containing stavudine or zidovudine and who have evidence of impaired mitochondrial function and insulin resistance.
详细描述
Treatment of HIV infection with nucleoside analogue reverse transcriptase inhibitors (NRTIs) has been associated with numerous toxicities that have been attributed to impaired mitochondrial function secondary to a reduction in the levels of mitochondrial DNA (mtDNA). Abnormalities in mitochondrial function have been implicated in the development of insulin resistance in patients with HIV infection and have also been hypothesized to underlie many of the pathophysiologic features of type 2 diabetes mellitus in non-HIV infected individuals.
Uridine, a pyrimidine nucleoside that plays an essential role in the synthesis of RNA and other key physiologic processes, has been proposed as a therapy for NRTI-induced mitochondrial dysfunction. Uridine supplementation protected bone marrow cells from the toxicity of zidovudine, normalized the growth of neurons exposed to NRTIs, and abrogated mitochondrial toxicity of NRTIs in HepG2 cells in vitro. A food supplement called NucleomaxX®, extracted from the stem of sugar cane, raises plasma uridine concentrations to levels known to prevent mitochondrial toxicity in vitro. In a recent case report, oral administration of uridine, given in the form of NucleomaxX®, ameliorated the mitochondrial toxicity caused by stavudine and led to improvements in myalgias and liver and muscle enzymes, despite continuing treatment with stavudine. In a clinical study of 14 HIV-infected patients treated with stavudine or zidovudine, NucleomaxX® led to improved hepatic mitochondrial function as assessed by the 13C-methionine breath test.
We will perform a randomized double-blind placebo-controlled study in 20 HIV-positive subjects who are currently undergoing treatment with antiretroviral regimens containing stavudine or zidovudine and who have evidence of impaired mitochondrial function and insulin resistance. Subjects will be hospitalized in the SFGH CTSI Clinical Research Center (CCRC) for 6 days to undergo comprehensive metabolic studies. Subjects will then be randomized, in a 1:1 fashion, to receive either NucleomaxX® or placebo for two months, after which they will repeat the 6-day CCRC-based assessments. This study is designed to test the hypothesis that, in comparison to placebo, uridine supplementation will enhance mitochondrial function, and this will be associated with concomitant improvements in glucose and lipid metabolism.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Confirmed HIV-1 infection
- •HIV-1 RNA <10,000 copies/mL within 30 days of study entry
- •Treatment with stavudine or zidovudine for at least 12 months prior to entry and no plan to discontinue for the duration of the study
- •Stable antiretroviral regimen for at least 3 months prior to entry and no plan to change antiretroviral therapy for the duration of the study
- •Mitochondrial dysfunction as evidenced by a fasting plasma lactate level > 1.5 mmol/L
- •Insulin resistance as evidenced by a HOMA-IR > 2.77 as calculated from fasting blood samples (for glucose and insulin) obtained during the screening visit
- •Karnofsky performance score >= 80
- •Women who are on stable regimens of hormonal contraceptives or hormone replacement therapy for at least 6 months prior to enrollment may participate
- •Men who are on stable doses of testosterone replacement therapy for 6 months prior to enrollment may participate
- •Subjects on a stable dose of lipid lowering agents for 6 months prior to enrollment may participate
排除标准
- •Serum creatinine and blood urea nitrogen > 1.5 upper limit of normal (ULN)
- •Direct bilirubin >2 X ULN
- •AST (SGOT) or ALT (SGPT) >5 x ULN
- •Hgb < 8.5 g/dL
- •Abnormal hepatitis B or C serology
- •A clinical diagnosis of diabetes mellitus or a fasting glucose > 126 mg/dl
- •Physical or functional obstruction to food intake or impaired absorption
- •A clinically suspected concomitant treatable infection that has not yet been treated
- •An opportunistic infection within the preceding 30 days
- •Pregnancy
- •Treatment with growth hormone, anabolic steroids (including supraphysiologic doses of testosterone), glucocorticoids, insulin, sulfonylureas, metformin, thiazolidinediones, or appetite stimulants within preceding 6 months
- •Dementia, active drug or alcohol abuse or dependence, or other conditions that would preclude adherence to the protocol or the ability to provide informed consent.
- •Any other condition that, in the opinion of the investigators, would put the subject at risk
研究组 & 干预措施
1
NucleomaxX
干预措施: NucleomaxX (contains uridine) (Drug)
2
Placebo
干预措施: NucleomaxX (contains uridine) (Drug)
结局指标
主要结局
Change in insulin sensitivity as measured by euglycemic hyperinsulinemic clamp (with simultaneous stable isotope tracer studies)
时间窗: 2 months
次要结局
- Adverse effects(continuously)
- Change in body composition (DEXA and CT imaging)(2 months)
- Change in insulin secretion (frequently sampled intravenous glucose tolerance test)(2 months)
- Change in resting energy expenditure (indirect calorimetry)(2 months)
- Change in markers of oxidative stress(2 months)
- Change in mtDNA levels (measured in muscle biopsy)(2 months)
- Change in HIV disease markers(2 months)
- Laboratory based toxicity(continuously)
- Adherence(continuously)
研究者
Morris Schambelan
Emeritus Professor of Medicine
National Center for Complementary and Integrative Health (NCCIH)