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

NCT00471614 | Completed Phase 2 DMC

• 1 other identifier: R21AT003374-01A1
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief 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 function and insulin resistance.

Conditions

HIV Infections; Insulin Resistance; Hyperlactatemia

Keywords

HIV; AIDS; uridine; mitochondria; insulin resistance; Treatment Experienced

Outcome Measures

Primary Outcomes (1)

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

  2 months

Secondary Outcomes (9)

• 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

Study Arms (2)

1

EXPERIMENTAL

NucleomaxX

Drug: NucleomaxX (contains uridine)

2

PLACEBO COMPARATOR

Placebo

Drug: NucleomaxX (contains uridine)

Interventions

NucleomaxX (contains uridine) DRUG

Escalated doses of NucleomaxX tid

1; 2

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Center for Complementary and Integrative Health (NCCIH): lead

Study Sites (1)

University of California San Francisco

San Francisco, California, 94110, United States

Location

Related Publications (6)

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

  PMID: 16152713 BACKGROUND

• 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.

  PMID: 14640394 BACKGROUND

• 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.

  PMID: 3190201 BACKGROUND

• 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.

  PMID: 8232219 BACKGROUND

• 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.

  PMID: 16847412 BACKGROUND

• 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.

  PMID: 15096820 BACKGROUND

MeSH Terms

Conditions

HIV Infections; Insulin Resistance; Hyperlactatemia; Acquired Immunodeficiency Syndrome

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Slow Virus Diseases

Study Officials

• Morris Schambelan, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Emeritus Professor of Medicine

Study Record Dates

• First Submitted: May 8, 2007
• First Posted: May 10, 2007
• Study Start: April 1, 2007
• Primary Completion: January 1, 2012
• Study Completion: January 1, 2012
• Last Updated: May 16, 2012

Record last verified: 2012-05

Locations

US (1)