Clinical trial NCT00307164: Effects of a Uridine Supplement on HIV Infected Adults With Lipoatrophy
Official title: A Phase II/III, Randomized, Double-Blind, Placebo-Controlled Trial of Uridine Supplementation in HIV Lipoatrophy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: HIV Infections
Lipoatrophy
Keywords: Treatment Experienced
Uridine
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2006-03-27
Enrollment: 167
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Lipoatrophy, the loss of body fat from particular areas of the body, is a common side effect of antiretroviral therapy (ART). The purpose of this study was to determine the effectiveness of uridine supplementation in treating HIV infected individuals on stable ART with lipoatrophy.

Detailed description: Lipoatrophy is a distressing long-term complication of ART and is associated with decreased quality of life, an increased risk of cardiovascular disease, and nonadherence to ART. The cause of lipoatrophy in HIV-infected individuals receiving ART is not completely understood. However, past research suggests that mitochondrial toxicity in subcutaneous adipose tissue caused by thymidine analogue nucleoside analogues may be responsible for the development of lipoatrophy.

Uridine is a nucleoside that has been shown to be an effective supplement in treating individuals with mitochondrial toxicity. NucleomaxX is a food supplement that consists of mitocnol, a sugar cane extract that has a high content of nucleosides, including uridine. The purpose of this study was to evaluate the effects of uridine supplementation in the form of NucleomaxX on limb fat in HIV-infected individuals receiving stable ART containing stavudine (d4T) or zidovudine (ZDV). In addition, this study evaluated the safety and tolerability of NucleomaxX.

This study lasted for 48 weeks. Participants were randomly assigned to one of two treatment arms, stratified by d4T or ZDV use. Arm A participants received NucleomaxX for uridine, while Arm B participants received a placebo for NucleomaxX. Participants in both arms received their assigned intervention three times per day, every other day, for the duration of the study. There were 8 study visits over the 48-week study duration. Blood collection and a physical exam occurred at all study visits, and participants completed an adherence assessment at most visits. Participants underwent dual energy X-ray absorptiometry scans (DEXA) within 14 days prior to or following the screening visit and at other selected visits. Specific fasting tests for glucose and lipid levels occurred at selected visits. ART was not provided by this study.

Eligibility criteria: Inclusion Criteria:

* HIV-1 infected
* Stable ART containing zidovudine or stavudine for at least 12 consecutive weeks prior to study entry
* Cumulative ART with zidovudine or stavudine for at least 24 weeks prior to study entry
* Viral load of 5,000 copies/ml or less within 45 days prior to study entry
* Lipoatrophy in at least two of the following areas: face, arms, legs, OR buttocks
* Not planning to add to or change current vitamin supplementation
* Willing to use acceptable forms of contraception

Exclusion Criteria:

* Life expectancy of less than 12 months
* Currently enrolled in or planning to enroll in an ART interruption study
* Plans to change current ART regimen
* Liver failure at anytime prior to study entry
* Greater than Grade 2 diarrhea or vomiting within 7 days prior to study entry
* Current AIDS-defining opportunistic infection or illness. Individuals with cutaneous Kaposi's sarcoma not requiring chemotherapy are not excluded.
* Currently receiving insulin or oral hypoglycemic products for diabetes mellitus
* Systemic cancer chemotherapy or immunomodulating agents within 30 days prior to study entry
* Systemic steroids for a cumulative duration of longer than 4 weeks within the 6 months prior to study entry
* Known allergy or sensitivity to study drug or any of its components
* Severe lactose intolerance
* Current drug or alcohol abuse or dependence
* Clinically significant illness requiring systemic treatment or hospitalization
* Chronic disability or serious illness that may affect body composition
* Received an investigational drug other than NucleomaxX or uridine for lipoatrophy within 30 days prior to study entry
* Certain abnormal laboratory values
* Pregnancy or breastfeeding

Primary outcomes:
measure: Change in Limb Fat (g) From Baseline
timeFrame: Baseline and Week 48
Secondary outcomes:
measure: Time to Safety Events (Signs/Symptoms or Laboratory Abnormalities)
timeFrame: Through Week 48
measure: Number of Subjects Discontinuing Study Medication
timeFrame: Through Week 48
measure: Change in Limb Fat From Baseline (Week 24 - Baseline)
timeFrame: Baseline and Week 24
measure: HIV-1 RNA Level
timeFrame: At Week 48
measure: Change in CD4+ Count From Baseline (Week 48 - Baseline)
timeFrame: Baseline and Week 48
measure: Change in Fasting Lactate From Baseline (Week 48 - Baseline)
timeFrame: Baseline and Week 48
measure: Change in Fasting Glucose From Baseline (Week 48 - Baseline)
timeFrame: Baseline and Week 48
measure: Change in Fasting Total Cholesterol From Baseline (Week 48 - Baseline)
timeFrame: Baseline and Week 48
measure: Change in Fasting High-density Lipoprotein (HDL) Cholesterol From Baseline (Week 48 - Baseline)
timeFrame: Baseline and Week 48
measure: Change in Fasting Non-HDL Cholesterol From Baseline (Week 48 - Baseline)
timeFrame: Baseline and Week 48
measure: Change in Fasting Low-density Lipoprotein (LDL) Cholesterol From Baseline (Week 48 - Baseline)
timeFrame: Baseline and Week 48
measure: Change in Fasting Triglycerides From Baseline (Week 48 - Baseline)
timeFrame: Baseline and Week 48
measure: Change in Hemoglobin From Baseline (Week 48 - Baseline)
timeFrame: Baseline and Week 48
measure: Change in Leukocytes From Baseline (Week 48 - Baseline)
timeFrame: Baseline and Week 48
measure: Change in Creatine Kinase From Baseline (Week 48 - Baseline)
timeFrame: Baseline and Week 48
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama Therapeutics CRS
state: Alabama
city: Los Angeles
country: United States
facility: USC CRS
state: California
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS
state: California
city: Palo Alto
country: United States
facility: Stanford CRS
state: California
city: San Diego
country: United States
facility: Ucsd, Avrc Crs
state: California
city: Torrance
country: United States
facility: Harbor-UCLA Med. Ctr. CRS
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS
state: Colorado
city: Atlanta
country: United States
facility: The Ponce de Leon Ctr. CRS
state: Georgia
city: Honolulu
country: United States
facility: Univ. of Hawaii at Manoa, Leahi Hosp.
state: Hawaii
city: Chicago
country: United States
facility: Rush Univ. Med. Ctr. ACTG CRS
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Univ. School of Medicine, Infectious Disease Research Clinic
state: Indiana
city: Baltimore
country: United States
facility: Johns Hopkins Adult AIDS CRS
state: Maryland
city: Minneapolis
country: United States
facility: University of Minnesota, ACTU
state: Minnesota
city: New York
country: United States
facility: Beth Israel Med. Ctr., ACTU
state: New York
city: New York
country: United States
facility: NY Univ. HIV/AIDS CRS
state: New York
city: New York
country: United States
facility: Cornell CRS
state: New York
city: New York
country: United States
facility: HIV Prevention & Treatment CRS
state: New York
city: Rochester
country: United States
facility: Trillium Health ACTG CRS
state: New York
city: Rochester
country: United States
facility: Univ. of Rochester ACTG CRS
state: New York
city: Chapel Hill
country: United States
facility: Unc Aids Crs
state: North Carolina
city: Durham
country: United States
facility: Duke Univ. Med. Ctr. Adult CRS
state: North Carolina
city: Cincinnati
country: United States
facility: Univ. of Cincinnati CRS
state: Ohio
city: Cleveland
country: United States
facility: Case CRS
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth CRS
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Medical Center
state: Ohio
city: Pittsburgh
country: United States
facility: Pitt CRS
state: Pennsylvania
city: Providence
country: United States
facility: The Miriam Hosp. ACTG CRS
state: Rhode Island
city: Nashville
country: United States
facility: Vanderbilt Therapeutics CRS
state: Tennessee
city: Seattle
country: United States
facility: University of Washington AIDS CRS
state: Washington
city: San Juan
country: Puerto Rico
facility: Puerto Rico-AIDS CRS
Study officials:
affiliation: Division of Infectious Diseases, Case Western Reserve University
name: Grace A. McComsey, MD
role: STUDY_CHAIR
affiliation: New York University
name: Judith A. Aberg, MD
role: STUDY_CHAIR
References:
citation: Koch EC, Schneider J, Weis R, Penning B, Walker UA. Uridine excess does not interfere with the antiretroviral efficacy of nucleoside analogue reverse transcriptase inhibitors. Antivir Ther. 2003 Oct;8(5):485-7. No abstract available.
citation: McComsey GA, Walker UA. Role of mitochondria in HIV lipoatrophy: insight into pathogenesis and potential therapies. Mitochondrion. 2004 Jul;4(2-3):111-8. doi: 10.1016/j.mito.2004.05.008.
citation: Nolan D, Hammond E, Martin A, Taylor L, Herrmann S, McKinnon E, Metcalf C, Latham B, Mallal S. Mitochondrial DNA depletion and morphologic changes in adipocytes associated with nucleoside reverse transcriptase inhibitor therapy. AIDS. 2003 Jun 13;17(9):1329-38. doi: 10.1097/00002030-200306130-00007.
citation: Walker UA, Venhoff N. Uridine in the prevention and treatment of NRTI-related mitochondrial toxicity. Antivir Ther. 2005;10 Suppl 2:M117-23.
citation: McComsey GA, Walker UA, Budhathoki CB, Su Z, Currier JS, Kosmiski L, Naini LG, Charles S, Medvik K, Aberg JA; AIDS Clinical Trials Group A5229 Team. Uridine supplementation in the treatment of HIV lipoatrophy: results of ACTG 5229. AIDS. 2010 Oct 23;24(16):2507-15. doi: 10.1097/QAD.0b013e32833ea9bc.