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AzTrials

HIV InfectionsPhase 2NCT00471614

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

A Phase 2 study testing NucleomaxX (contains uridine) in people with HIV Infections and Insulin Resistance, run by National Center for Complementary and Integrative Health (NCCIH) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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… Read more about this study

Who is it for?
Ages 18 to 65 years
What is being tested?
NucleomaxX (contains uridine)
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
3 participants
Where
1 siteUnited States
Study dates
Apr 2007to Jan 2012
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 65 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 10Show fewer
  • 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

Who cannot join

  • 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
Show all 14Show fewer
  • 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

Trial locations and contacts

1 site in 1 country.

United States1 site

  • University of California San Francisco

    San Francisco, California, 94110

Other trials in United States

About this study

Official title: 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.

Read the detailed description

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.

Being tested
NucleomaxX (contains uridine)
Keywords
HIV, AIDS, uridine, mitochondria, insulin resistance, Treatment Experienced
Medical subject headings
HIV Infections, Insulin Resistance, Hyperlactatemia, Acquired Immunodeficiency Syndrome

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • NucleomaxX (contains uridine)Drug

    Escalated doses of NucleomaxX tid

Study groups in NCT00471614
Study groupRoleWhat they receive
1ExperimentalNucleomaxX
Receives: Drug: NucleomaxX (contains uridine)
2Placebo comparatorPlacebo
Receives: Drug: NucleomaxX (contains uridine)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in insulin sensitivity as measured by euglycemic hyperinsulinemic clamp (with simultaneous stable isotope tracer studies)

    Measured: 2 months

Secondary outcomes (9)

  1. Change in body composition (DEXA and CT imaging)

    Measured: 2 months

  2. Change in insulin secretion (frequently sampled intravenous glucose tolerance test)

    Measured: 2 months

  3. Change in resting energy expenditure (indirect calorimetry)

    Measured: 2 months

  4. Change in markers of oxidative stress

    Measured: 2 months

  5. Change in mtDNA levels (measured in muscle biopsy)

    Measured: 2 months

  6. Change in HIV disease markers

    Measured: 2 months

  7. Adverse effects

    Measured: continuously

  8. Laboratory based toxicity

    Measured: continuously

  9. Adherence

    Measured: continuously

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted10 May 2007 (estimated)
  2. Study startApr 2007
  3. Primary completionJan 2012
  4. Study completionJan 2012

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
3 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00471614
Sponsor's protocol ID
R21AT003374-01A1
Status last verified
May 2012
First submitted
8 May 2007
Last updated
16 May 2012
Results posted
No
Data monitoring committee
Yes

Publications

  • Walker UA, Venhoff N. Uridine in the prevention and treatment of NRTI-related mitochondrial toxicity. Antivir Ther. 2005;10 Suppl 2:M117-23.

    PubMed 16152713

  • Walker UA, Venhoff N, Koch EC, Olschewski M, Schneider J, Setzer B. Uridine abrogates mitochondrial toxicity related to nucleoside analogue reverse transcriptase inhibitors in HepG2 cells. Antivir Ther. 2003 Oct;8(5):463-70.

    PubMed 14640394

  • Sommadossi JP, Carlisle R, Schinazi RF, Zhou Z. Uridine reverses the toxicity of 3'-azido-3'-deoxythymidine in normal human granulocyte-macrophage progenitor cells in vitro without impairment of antiretroviral activity. Antimicrob Agents Chemother. 1988 Jul;32(7):997-1001. doi: 10.1128/AAC.32.7.997.

    PubMed 3190201

  • Keilbaugh SA, Hobbs GA, Simpson MV. Anti-human immunodeficiency virus type 1 therapy and peripheral neuropathy: prevention of 2',3'-dideoxycytidine toxicity in PC12 cells, a neuronal model, by uridine and pyruvate. Mol Pharmacol. 1993 Oct;44(4):702-6.

    PubMed 8232219

  • Banasch M, Goetze O, Knyhala K, Potthoff A, Schlottmann R, Kwiatek MA, Bulut K, Schmitz F, Schmidt WE, Brockmeyer NH. Uridine supplementation enhances hepatic mitochondrial function in thymidine-analogue treated HIV-infected patients. AIDS. 2006 Jul 13;20(11):1554-6. doi: 10.1097/01.aids.0000237373.38939.14.

    PubMed 16847412

  • Walker UA, Langmann P, Miehle N, Zilly M, Klinker H, Petschner F. Beneficial effects of oral uridine in mitochondrial toxicity. AIDS. 2004 Apr 30;18(7):1085-6. doi: 10.1097/00002030-200404300-00025. No abstract available.

    PubMed 15096820

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing NucleomaxX (contains uridine) in people with HIV Infections and Insulin Resistance, run by National Center for Complementary and Integrative Health (NCCIH) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 16 May 2012. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in insulin sensitivity as measured by euglycemic hyperinsulinemic clamp (with simultaneous stable isotope tracer studies) (time frame: 2 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00471614, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 May 2012.

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