Effects of Uridine Supplementation on Metabolic Side Effects of Stavudine and Zidovudine

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Morris Schambelan, National Center for Complementary and Alternative Medicine (NCCAM)
ClinicalTrials.gov Identifier:
NCT00471614
First received: May 8, 2007
Last updated: May 15, 2012
Last verified: May 2012

May 8, 2007
May 15, 2012
April 2007
January 2012   (final data collection date for primary outcome measure)
Change in insulin sensitivity as measured by euglycemic hyperinsulinemic clamp (with simultaneous stable isotope tracer studies) [ Time Frame: 2 months ] [ Designated as safety issue: Yes ]
Change in insulin sensitivity as measured by euglycemic hyperinsulinemic clamp (with simultaneous stable isotope tracer studies)
Complete list of historical versions of study NCT00471614 on ClinicalTrials.gov Archive Site
  • Change in body composition (DEXA and CT imaging) [ Time Frame: 2 months ] [ Designated as safety issue: Yes ]
  • Change in insulin secretion (frequently sampled intravenous glucose tolerance test) [ Time Frame: 2 months ] [ Designated as safety issue: No ]
  • Change in resting energy expenditure (indirect calorimetry) [ Time Frame: 2 months ] [ Designated as safety issue: No ]
  • Change in markers of oxidative stress [ Time Frame: 2 months ] [ Designated as safety issue: No ]
  • Change in mtDNA levels (measured in muscle biopsy) [ Time Frame: 2 months ] [ Designated as safety issue: No ]
  • Change in HIV disease markers [ Time Frame: 2 months ] [ Designated as safety issue: Yes ]
  • Adverse effects [ Time Frame: continuously ] [ Designated as safety issue: Yes ]
  • Laboratory based toxicity [ Time Frame: continuously ] [ Designated as safety issue: Yes ]
  • Adherence [ Time Frame: continuously ] [ Designated as safety issue: No ]
  • Change in body composition (DEXA and CT imaging)
  • Change in insulin secretion (frequently sampled intravenous glucose tolerance test)
  • Change in resting energy expenditure (indirect calorimetry)
  • Change in markers of oxidative stress
  • Change in mtDNA levels (measured in muscle biopsy)
  • Change in HIV disease markers
  • Adverse effects
  • Laboratory based toxicity
  • Adherence
Not Provided
Not Provided
 
Effects of Uridine Supplementation on Metabolic Side Effects of Stavudine and Zidovudine
Uridine Supplementation, Mitochondrial Function, and Glucose Metabolism in HIV

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.

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.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
  • HIV Infections
  • Insulin Resistance
  • Hyperlactatemia
Drug: NucleomaxX (contains uridine)
Escalated doses of NucleomaxX tid
  • Experimental: 1
    NucleomaxX
    Intervention: Drug: NucleomaxX (contains uridine)
  • Placebo Comparator: 2
    Placebo
    Intervention: Drug: NucleomaxX (contains uridine)

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
3
January 2012
January 2012   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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
  • Ascites
  • 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
Both
18 Years to 65 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00471614
R21 AT003374-01A1
Yes
Morris Schambelan, National Center for Complementary and Alternative Medicine (NCCAM)
National Center for Complementary and Alternative Medicine (NCCAM)
Not Provided
Principal Investigator: Morris Schambelan, MD University of California, San Francisco
National Center for Complementary and Alternative Medicine (NCCAM)
May 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP