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| ID | Type | Description | Link |
|---|---|---|---|
| R01AI060484 | U.S. NIH Grant/Contract | View source |
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HIV lipoatrophy is a condition marked by fat loss; it occurs in many patients taking antiretroviral (ARV) therapy that includes nucleoside reverse transcriptase inhibitors (NRTIs). Lipoatrophy may be related to mitochondrial toxicity, a condition that can damage the heart, nerves, muscles, kidneys, and liver, and can affect the body's ability to produce energy. NucleomaxX is a food supplement consisting of a sugar cane extract high in nucleosides, which are building blocks that may counteract the negative effects of NRTIs. Tenofovir disoproxil fumarate (TDF) is an NRTI that may cause less lipoatrophy than other drugs in its class, such as zidovudine (ZDV) or stavudine (d4T). The purpose of this study is to determine whether nucleoside supplementation with NucleomaxX and substitution of TDF for ZDV or d4T in an ARV regimen can reverse fat loss caused by mitochondrial toxicity in HIV infected adults.
Study hypotheses: 1) The substitution of TDF for d4T or ZDV in patients with HIV lipoatrophy will result in an increase in mitochondrial DNA content in fat, skeletal muscle, and peripheral blood mononuclear cells (PBMCs), which in turn will lead to an improvement in mitochondrial function as assessed by electron transport chain (ETC) and oxidative phosphorylation pathway (OXPHOS) activity. The latter should lead to a decrease in fat apoptosis and in mitochondrial and lipid oxidative damage biomarkers. 2) Supplementation with uridine (via NucleomaxX) will increase mtDNA content in adipose tissue and increase body fat content.
NRTIs are an important part of many ARV regimens used to treat HIV infected patients; however, the relationship between NRTI-induced mitochondrial dysfunction and lipoatrophy is still unclear and requires additional research. Additionally, the relationship between the gain in dual-energy x-ray absorptiometry (DEXA)-measured limb fat and mitochondrial DNA (mtDNA) content, mitochondrial function, fat apoptosis, and oxidative damage will also be examined in this study.
Patients will participate in this study for 48 weeks. Participants will be randomly assigned to one of two groups. Group 1 patients will receive NucleomaxX every other day. Group 2 patients will substitute TDF for ZDV or d4T every day in their current stable NRTI-containing ARV regimen. NucleomaxX will be provided to Group 1 patients, but TDF or any other ARV will not be provided by this study.
There will be 10 study visits, which will occur at study entry and Weeks 2, 4, 8, 12, 18, 24, 30, 36, and 48. Blood collection will occur at all visits. Additionally, urine collection, DEXA scans, and fat biopsies will be done at study entry and Weeks 24 and 48.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| uridine supplementation | Experimental | NucleomaxX 36 grams TID every other day |
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| Switch to Tenofovir | Active Comparator | Switch of AZT or d4T to Tenofovir Disoproxil Fumarate |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| NucleomaxX | Drug | NucleomaxX 36 grams TID every other day |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in Fat mtDNA Content | Subcutaneous abdominal fat mitochondrial DNA (mtDNA) | Baseline to Week 48 |
| Change in PBMC mtDNA | Peripheral blood mononuclear cell (PBMC) mitochondrial DNA (mtDNA), measured in copies/cell | Baseline to Week 48 |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Limb Fat | Change in limb fat as measured by dual-energy x-ray absorbtiometry (DEXA) scan | Baseline to Week 48 |
| Change in Trunk Fat | Change in trunk fat as measured by dual-energy x-ray absorbtiometry (DEXA) scan |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Grace A. McComsey, MD | Case Western Reserve University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Hospitals of Cleveland | Cleveland | Ohio | 44106 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 17538545 | Result | McComsey GA, O'Riordan M, Setzer B, Lebrecht D, Baron E, Walker UA. Uridine supplementation in HIV lipoatrophy: pilot trial on safety and effect on mitochondrial indices. Eur J Clin Nutr. 2008 Aug;62(8):1031-7. doi: 10.1038/sj.ejcn.1602793. Epub 2007 May 30. | |
| 22293126 | Derived | McComsey GA, O'Riordan M, Choi J, Libutti D, Rowe D, Storer N, Harrill D, Gerschenson M. Mitochondrial function, inflammation, fat and bone in HIV lipoatrophy: randomized study of uridine supplementation or switch to tenofovir. Antivir Ther. 2012;17(2):347-53. doi: 10.3851/IMP1928. Epub 2011 Oct 13. |
| Label | URL |
|---|---|
| click here for more information about uridine supplementation or switch to tenofovir. | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Uridine Supplementation | NucleomaxX 36 grams TID every other day NucleomaxX: NucleomaxX 36 grams TID every other day |
| FG001 | Switch to TDF | Switch of AZT or d4T to tenofovir Tenofovir disoproxil fumarate: Switch thymidine NRTI to tenofovir |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Tenofovir Disoproxil Fumarate | Drug | Switch of thymidine nucleoside reverse transcriptase inhibitors to Tenofovir Disoproxil Fumarate |
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| Baseline to Week 48 |
| Change in Lumbar Spine Bone Mineral Density (BMD) | Change in lumbar spine bone mineral density (BMD) as measured by dual-energy x-ray absorbtiometry (DEXA) scan | Baseline to Week 48 |
| Change in Hip Bone Mineral Density (BMD) | Change in hip bone mineral density (BMD) as measured by dual-energy x-ray absorbtiometry (DEXA) scan | Baseline to Week 48 |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Uridine Supplementation | NucleomaxX 36 grams TID every other day NucleomaxX: NucleomaxX 36 grams TID every other day |
| BG001 | Switch to TDF | Switch of AZT or d4T to tenofovir Tenofovir disoproxil fumarate: Switch thymidine NRTI to tenofovir |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Age, Continuous | Median | Full Range | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Region of Enrollment | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Fat mtDNA Content | Subcutaneous abdominal fat mitochondrial DNA (mtDNA) | Posted | Median | Inter-Quartile Range | copies/cell | Baseline to Week 48 |
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| Primary | Change in PBMC mtDNA | Peripheral blood mononuclear cell (PBMC) mitochondrial DNA (mtDNA), measured in copies/cell | Posted | Median | Inter-Quartile Range | copies/cell | Baseline to Week 48 |
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| Secondary | Change in Limb Fat | Change in limb fat as measured by dual-energy x-ray absorbtiometry (DEXA) scan | Posted | Median | Inter-Quartile Range | limb fat (kg) | Baseline to Week 48 |
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| Secondary | Change in Trunk Fat | Change in trunk fat as measured by dual-energy x-ray absorbtiometry (DEXA) scan | Posted | Median | Inter-Quartile Range | trunk fat (kg) | Baseline to Week 48 |
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| ||||||||||||||||||||||||||||||
| Secondary | Change in Lumbar Spine Bone Mineral Density (BMD) | Change in lumbar spine bone mineral density (BMD) as measured by dual-energy x-ray absorbtiometry (DEXA) scan | Posted | Median | Inter-Quartile Range | lumbar spine BMD, g/cm^2 | Baseline to Week 48 |
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| ||||||||||||||||||||||||||||||
| Secondary | Change in Hip Bone Mineral Density (BMD) | Change in hip bone mineral density (BMD) as measured by dual-energy x-ray absorbtiometry (DEXA) scan | Posted | Median | Inter-Quartile Range | hip BMD, g/cm^2 | Baseline to Week 48 |
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Weeks 4,8,12,18 and 36
Study evaluation was conducted at study entry and week 48; and additional safety visits were carried out at weeks 4,8,12,18 and 36 for the purpose of clinical and laboratory monitoring for toxicities, intolerance and adherance.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Uridine Supplementation | NucleomaxX 36 grams TID every other day NucleomaxX: NucleomaxX 36 grams TID every other day | 0 | 26 | 8 | 26 | 18 | 26 |
| EG001 | Switch to TDF | Switch of AZT or d4T to tenofovir Tenofovir disoproxil fumarate: Switch thymidine NRTI to tenofovir | 0 | 24 | 6 | 24 | 13 | 24 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypoglycemia Gr. 3 | Metabolism and nutrition disorders | Systematic Assessment |
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| Abnormal phos. Gr. 3 | General disorders | Systematic Assessment |
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| Renal calculus Gr. 3 | General disorders | Systematic Assessment |
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| Elevated CK Gr. 3 & 4 | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Pancreatitis Gr. 3 | Endocrine disorders | Systematic Assessment |
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| Vertigo Gr. 3 | Ear and labyrinth disorders | Systematic Assessment |
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| Hypercholesterolem Gr. 3 | Cardiac disorders | Systematic Assessment |
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| Diarrhea Gr. 3 | Gastrointestinal disorders | Systematic Assessment |
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| Hypertrigliceridemia Gr. 3 & 4 | General disorders | Systematic Assessment |
| ||
| Abnormal AST Gr. 3 | General disorders | Systematic Assessment |
| ||
| Dysuria Gr. 3 | Renal and urinary disorders | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Incisional hematoma Gr. 1 & 2 | Blood and lymphatic system disorders | Systematic Assessment |
| ||
| Infected Incisional hematoma Gr. 2 | General disorders | Systematic Assessment |
| ||
| Incisional seroma Gr. 1 & 2 | General disorders | Systematic Assessment |
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| Hyperglycemia Gr. 1 & 2 | Metabolism and nutrition disorders | Systematic Assessment |
| ||
| Hypoglycemia Gr. 1 & 2 | Metabolism and nutrition disorders | Systematic Assessment |
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| Hypophosphatemia Gr. 2 | General disorders | Systematic Assessment |
| ||
| Sinusitis Gr. 1 | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| ||
| Tachycardia Gr. 2 | Cardiac disorders | Systematic Assessment |
| ||
| Thrombocytopenia Gr. 2 | Vascular disorders | Systematic Assessment |
| ||
| Elevated triglycerides Gr. 2 | General disorders | Systematic Assessment |
| ||
| URI Gr. 2 | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| ||
| Elevated AST Gr. 2 | General disorders | Systematic Assessment |
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| Diarhhea | Gastrointestinal disorders | Systematic Assessment |
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| Neurtropenia Gr. 2 | Blood and lymphatic system disorders | Systematic Assessment |
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| Nausea | General disorders | Systematic Assessment |
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| Otitis Gr. 2 | Ear and labyrinth disorders | Systematic Assessment |
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| Prob. Herpes simplex Gr. 2 | General disorders | Systematic Assessment |
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| Prob. Renal calculus Gr. 2 | Renal and urinary disorders | Systematic Assessment |
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| Rash/Bactrim allergy Gr. 1 | Gastrointestinal disorders | Systematic Assessment |
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| Elevated CK Gr. 2 | General disorders | Systematic Assessment |
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| Abnormal LDL Chol Gr. 2 | Vascular disorders | Systematic Assessment |
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| Herpes zoster Gr. 2 | General disorders | Systematic Assessment |
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| Incisional neuritis Gr. 2 | General disorders | Systematic Assessment |
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| Gross hematuria Gr. 2 | Blood and lymphatic system disorders | Systematic Assessment |
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| Abnormal cholesterol Gr. 2 | Vascular disorders | Systematic Assessment |
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| Abnormal Glucose Gr. 1 & 2 | Metabolism and nutrition disorders | Systematic Assessment |
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| Abnormal ALT Gr. 2 | General disorders | Systematic Assessment |
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| Abnormal BMD/T score Gr. 2 | General disorders | Systematic Assessment |
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| Abnormal creatine Gr. 2 | General disorders | Systematic Assessment |
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| Abnormal FBS Gr. 2 | General disorders | Systematic Assessment |
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| Elevated LFTs Gr. 2 | General disorders | Systematic Assessment |
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| Chalazion left eye - Gr. 2 | Eye disorders | Systematic Assessment |
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Small sample size; Lack of control arm where tNRTI therapy was continued without any intervention; Adherence measured by sachet/pill count method.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Grace McComsey | University Hospitals Case Medical Center | 216-844-2739 | mccomsey.grace@clevelandactu.org |
| ID | Term |
|---|---|
| D015658 | HIV Infections |
| D008060 | Lipodystrophy |
| D008659 | Metabolic Diseases |
| D009748 | Nutrition Disorders |
| ID | Term |
|---|---|
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D007239 | Infections |
| D015229 | Sexually Transmitted Diseases, Viral |
| D012749 | Sexually Transmitted Diseases |
| D016180 | Lentivirus Infections |
| D012192 | Retroviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |
| D012875 | Skin Diseases, Metabolic |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D052439 | Lipid Metabolism Disorders |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D014529 | Uridine |
| D000068698 | Tenofovir |
| ID | Term |
|---|---|
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D012263 | Ribonucleosides |
| D063065 | Organophosphonates |
| D009943 | Organophosphorus Compounds |
| D009930 | Organic Chemicals |
| D000225 | Adenine |
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
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| >=65 years |
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| Male |
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