Reversing Tissue Fibrosis to Improve Immune Reconstitution in HIV
This study was designed to test the hypothesis that treatment of HIV infected subjects with losartan, an agent with specific anti-inflammatory and anti-fibrotic actions, will:
- reverse existing lymphoid tissue fibrosis,
- restore lymphoid tissue architecture,
- increase the number and improve the function of peripheral and lymphatic CD4 T cells,
- decrease levels of systemic immune activation (IA),
- decrease size of the HIV reservoir, and
- be safe and well tolerated.
調査の概要
詳細な説明
This is a randomized, double-blind, placebo-controlled trial of 50 HIV-1 infected individuals on stable ART randomized in a 1:1 ratio to losartan (50 mg orally daily titrated to 100 mg daily) vs placebo for 30 months. We plan to enroll a total of 63 HIV infected subjects to ensure that 50 complete the protocol. All HIV infected subjects will undergo biopsies of inguinal lymph node (LN) and gut associated lymphatic tissue (GALT) for primary endpoint analysis at baseline, 12 and 30 months after study enrollment. Blood will be collected at least quarterly throughout the study and an intensive blood pharmacokinetic (PK) study will be conducted at month 1. All HIV infected subjects will be vaccinated with the quadrivalent human papillomavirus (HPV) vaccine at months 23, 25 and 29.5 to measure immune function. 5 HIV uninfected control subjects will also be enrolled.
The primary endpoint is to determine the impact of losartan on lymphoid tissue fibrosis in HIV infected, ART treated adults. This will be determined by measuring the amount of collagen deposition in lymphoid tissues and the integrity of the FRCn using immunohistochemistry (IHC) and quantitative image analysis (QIA).
研究の種類
入学 (実際)
段階
- フェーズ2
連絡先と場所
研究場所
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Minnesota
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Minneapolis、Minnesota、アメリカ、55455
- University of Minnesota, Division of Infectious Diseases
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参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
HIV infected participants:
Inclusion Criteria:
Participants must meet all of the following inclusion criteria to participate in this study:
HIV-1 infected.
-≥ 18 years of age.
Baseline peripheral CD4+ T cell count 200-600 cells/mm3 for at least two measures over the 6 months prior to study enrollment.
-≥ 12 months of stable ART, defined as use of a given drug regimen without disruption lasting ≥ 1 week in the period leading up to study enrollment.
- HIV viral load (VL) < 50 copies/mL for at least two consecutive measures over the 6 months prior to study enrollment.
- No contraindication to proposed study procedures.
- Women of child-bearing potential must be willing to use a form of effective contraception for the duration of the study. Effective contraception includes hormonal injection, implant or oral medication, IUD, diaphragm, or cervical cap with spermicide. Condoms cannot be used as the sole form of contraception.
Exclusion Criteria: Participants meeting any of the following exclusion criteria at baseline will be excluded from study participation:
- Use of any immunomodulator within the 12 months prior to study enrollment. An immunomodulator for the purposes of this study is defined as a drug known to either diminish or augment a patient's immune system. Examples of these include, but are not limited to, systemic corticosteroids (use of topical steroids will be permitted), TNF-inhibitors, rituximab, cyclophosphamide, abatacept,cyclosporine, azathioprine, 6-mercaptopurine, methotrexate, sulfasalazine, cyclosporine, tacrolimus,sirolimus, and intravenous immune globulin.
- Current use of an ARB or ACEi.
- Current use of rifaximin, fluconazole or lithium given potential for drug interactions with losartan.
- Prior reaction or intolerance to an ARB or ACEi.
- Prior diagnosis of a chronic inflammatory disease with serologic or clinical evidence as diagnosed by a primary care physician or specialist. Examples of these include, but are not limited to, systemic lupus erythematosus, rheumatoid arthritis, scleroderma, Sjogren's syndrome, mixed connective tissue disease, psoriasis, polymyositis, dermatomyositis, vasculitis, sarcoidosis, Wegener's granulomatosis, giant cell arteritis, polyarteritis nodosa, gastrointestinal pemphigoid, eosinophilic colitis, Crohn's disease, ulcerative colitis, autoimmune hepatitis, and hepatitis C.
- Prior diagnosis of a connective tissue disease with genetic, serologic or clinical evidence as diagnosed by a primary care physician or specialist (Marfan's syndrome, Ehlers-Danlos syndrome).
- Baseline blood pressure < 110/70.
- Estimated Glomerular Filtration Rate (eGFR) of < 30ml/min/1.73 m2 within 4 weeks of study initiation or history of advanced renal disease.
- AST and/or ALT > 3 times the upper limit of normal within 4 weeks of study enrollment.
- Potassium > 5.0 within 4 weeks of study enrollment.
- Pregnancy.
- In women of childbearing age, unwillingness to use birth control for the duration of the study.
- Breast feeding.
- Prior vaccination with an HPV vaccine, including Cervarix (GlaxoSmithKline) or Gardasil (Merck).
- History of hypersensitivity or severe allergic reactions to yeast.
HIV-uninfected:
Inclusion Criteria
Participants must meet all of the following inclusion criteria to participate in this study:
HIV uninfected.
-≥ 18 years of age.
- No contraindication to proposed study procedures.
Exclusion Criteria: Participants meeting any of the following exclusion criteria at baseline will be excluded from study participation:
- Use of any immunomodulator within the 12 months prior to study enrollment (as defined above).
- Current use of an ARB or ACEi.
- Prior diagnosis of a chronic inflammatory disease with serologic or clinical evidence (as defined above).
- Prior diagnosis of a connective tissue disease with genetic, serologic or clinical evidence as diagnosed by a primary care physician or specialist (Marfan's syndrome, Ehlers-Danlos syndrome).
- Pregnancy.
研究計画
研究はどのように設計されていますか?
デザインの詳細
- 主な目的:処理
- 割り当て:ランダム化
- 介入モデル:並列代入
- マスキング:トリプル
武器と介入
参加者グループ / アーム |
介入・治療 |
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プラセボコンパレーター:シュガーピル
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one tablet by mouth daily
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実験的:ロサルタン
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Participants will start with 50 mg of losartan by mouth daily.
The dose will be increased to 100 mg by mouth daily after 14 days.
The maximal tolerable dosage (up to 100mg by mouth daily) will be continued for a total of 30 months.
他の名前:
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この研究は何を測定していますか?
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
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Collagen Deposition in LT
時間枠:30 months
|
The Impact of Losartan Treatment on Lymphoid Tissue (LT) Fibrosis will be determined by measuring the amount of collagen deposition in LT using immunohistochemistry (IHC) and quantitative image analysis (QIA).
LT will be obtained at baseline, month 12 and month 30.
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30 months
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Integrity of the Fibroblastic Reticular Cell Network (FRCn)
時間枠:30 months
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The Impact of Losartan Treatment on Lymphoid Tissue (LT) Fibrosis will be determined by measuring the Integrity of the fibroblastic reticular cell network (FRCn) using immunohistochemistry (IHC) and quantitative image analysis (QIA).
LT will be obtained at baseline, month 12 and month 30.
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30 months
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
---|---|---|
Frequency of CD4+ T Cells
時間枠:30 months
|
Impact of losartan on immune reconstitution and function will be determined by frequency of CD4+ T cells in LT using IHC.
|
30 months
|
Frequency TUNEL+CD3+CD8+ T Cells
時間枠:30 months
|
Impact of losartan on immune reconstitution and function will be determined by frequency of TUNEL+CD3+CD8+ T cells in LT using IHC.
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30 months
|
Frequency of Cells Expressing TGF-beta and Lymphotoxin-beta
時間枠:30 months
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Impact of losartan on immune reconstitution and function will be determined by frequency of cells expressing TGF-beta and lymphotoxin-beta in LT using IHC.
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30 months
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Serum Concentration of IL-7
時間枠:30 months
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Impact of losartan on immune reconstitution and function will be determine by serum concentrations of IL-7 measured with ELISA.
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30 months
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Serum Concentration of TGF-beta
時間枠:30 months
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Impact of losartan on immune reconstitution and function will be determine by serum concentrations of TGF-beta measured with ELISA.
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30 months
|
Immune Response to HPV Vaccination
時間枠:30 months
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Impact of losartan on immune reconstitution and function will be determine by measuring the immune response to HPV vaccination using flow cytometry to identify cells stimulated by specific HPV peptides.
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30 months
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Frequency of Activated T-cell Populations - Immunofluorescent Staining
時間枠:30 months
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The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the frequency of activated T-cell populations (specifically CD3+CD4+CD38+, CD3+,CD8+CD38+,CD4+Ki67+ and CD8+Ki67+ T cells) in LT using immunofluorescence staining
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30 months
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Percent of Activated T Cells in PBMCs - Flow Cytometry
時間枠:30 months
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The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the percentage of activated T cells in peripheral blood mononuclear cells (PBMCs) using flow cytometry.
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30 months
|
Percent of Activated Macrophages in PBMCs - Flow Cytometry
時間枠:30 months
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The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the percentage of activated macrophages in peripheral blood mononuclear cells (PBMCs) using flow cytometry.
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30 months
|
Percent of Activated Dendritic Cells in PBMCs - Flow Cytometry
時間枠:30 months
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The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the percentage of activated dendritic cells in peripheral blood mononuclear cells (PBMCs) using flow cytometry.
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30 months
|
Percent of Activated T Cells in LT - Flow Cytometry
時間枠:30 months
|
The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the percentage of activated T cells in lymphoid tissues (LT) using flow cytometry.
|
30 months
|
Percent of Activated Macrophages in LT - Flow Cytometry
時間枠:30 months
|
The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the percentage of activated macrophages in lymphoid tissues (LT) using flow cytometry.
|
30 months
|
Percent of Activated Dendritic Cells in LT - Flow Cytometry
時間枠:30 months
|
The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the percentage of activated dendritic cells in lymphoid tissues (LT) using flow cytometry.
|
30 months
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Intracellular Concentration of IL-17 in PBMCs
時間枠:30 months
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The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the intracellular levels of the inflammatory cytokine IL-17 in PBMCs using cytokine staining.
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30 months
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Intracellular Concentration of IFNg in PBMCs
時間枠:30 months
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The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the intracellular levels of the inflammatory cytokine IFNg in PBMCs using cytokine staining.
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30 months
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Intracellular Concentration of IL-2 in PBMCs
時間枠:30 months
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The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the intracellular levels of the inflammatory cytokine IL-2 in PBMCs using cytokine staining.
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30 months
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Intracellular Concentration of TNF in PBMCs
時間枠:30 months
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The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the intracellular levels of the inflammatory cytokine TNF in PBMCs using cytokine staining.
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30 months
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Intracellular Concentration of IL-10 in PBMCs
時間枠:30 months
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The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the intracellular levels of the inflammatory cytokine IL-10 in PBMCs using cytokine staining.
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30 months
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Intracellular Concentration of GM-CSF in PBMCs
時間枠:30 months
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The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the intracellular levels of the inflammatory cytokine GM-CSF in PBMCs using cytokine staining.
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30 months
|
Intracellular Concentration of IL-17 in LT
時間枠:30 months
|
The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the intracellular levels of the inflammatory cytokine IL-17 in lymphoid tissue (LT) using cytokine staining.
|
30 months
|
Intracellular Concentration of IFNg in LT
時間枠:30 months
|
The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the intracellular levels of the inflammatory cytokine IFNg in lymphoid tissue (LT) using cytokine staining.
|
30 months
|
Intracellular Concentration of IL-2 in LT
時間枠:30 months
|
The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the intracellular levels of the inflammatory cytokine IL-2 in lymphoid tissue (LT) using cytokine staining.
|
30 months
|
Intracellular Concentration of TNF in LT
時間枠:30 months
|
The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the intracellular levels of the inflammatory cytokine TNF in lymphoid tissue (LT) using cytokine staining.
|
30 months
|
Intracellular Concentration of IL-10 in LT
時間枠:30 months
|
The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the intracellular levels of the inflammatory cytokine IL-10 in lymphoid tissue (LT) using cytokine staining.
|
30 months
|
Intracellular Concentration of GM-CSF in LT
時間枠:30 months
|
The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the intracellular levels of the inflammatory cytokine GM-CSF in lymphoid tissue (LT) using cytokine staining.
|
30 months
|
Plasma Concentration of LPS
時間枠:30 months
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The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the plasma concentration of LPS by ELISA.
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30 months
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Plasma Concentration of sCD14
時間枠:30 months
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The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the plasma concentration of sCD14 by limulus assay.
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30 months
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Plasma Concentration of I-FABP
時間枠:30 months
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The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the plasma concentration of I-FABP using ELISA.
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30 months
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Plasma Concentration of IL-1b
時間枠:30 months
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The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the plasma concentration of IL-1b using ELISA.
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30 months
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Plasma Concentration of IL-1RA
時間枠:30 months
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The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the plasma concentration of IL-1RA using ELISA.
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30 months
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Plasma Concentration of IL-6
時間枠:30 months
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The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the plasma concentration of IL-6 using ELISA.
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30 months
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Plasma Concentration of TNF
時間枠:30 months
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The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the plasma concentration of TNF using ELISA.
|
30 months
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Plasma Concentration of Amyloid A
時間枠:30 months
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The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the plasma concentration of amyloid A using ELISA.
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30 months
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Plasma Concentration of CRP
時間枠:30 months
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The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the plasma concentration of CRP using ELISA.
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30 months
|
Plasma Concentration of D-dimer
時間枠:30 months
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The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the plasma concentration of D-dimer using ELISA.
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30 months
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Frequency of HIV RNA+ and DNA+ Cells in LN - Radiolabeled ISH
時間枠:30 months
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The Potential for Losartan to Reduce the Size of the Viral Reservoir will be assessed by determining the frequency of HIV RNA+ and DNA+ cells in LN using radiolabeled in situ hybridization (ISH).
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30 months
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Frequency of HIV RNA+ and DNA+ Cells in LN - RNAscopeTM in Situ Technology
時間枠:30 months
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The Potential for Losartan to Reduce the Size of the Viral Reservoir will be assessed by determining the frequency of HIV RNA+ and DNA+ cells in LN using RNAscopeTM in situ technology.
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30 months
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Frequency of HIV RNA+ and DNA+ Cells in GALT - Radiolabeled in Situ Hybridization (ISH)
時間枠:30 months
|
The Potential for Losartan to Reduce the Size of the Viral Reservoir will be assessed by determining the frequency of HIV RNA+ and DNA+ cells in GALT radiolabeled in situ hybridization (ISH).
|
30 months
|
Frequency of HIV RNA+ and DNA+ Cells in GALT - RNAscopeTM in Situ Technology
時間枠:30 months
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The Potential for Losartan to Reduce the Size of the Viral Reservoir will be assessed by determining the frequency of HIV RNA+ and DNA+ cells in GALT using RNAscopeTM in situ technology.
|
30 months
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Concentration of Losartan and Antiretrovirals (ARVs)
時間枠:30 months
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Potential Drug-drug Interactions Between Losartan and Antiretrovirals (ARVs) will be assessed by measuring levels of ARVs and losartan in plasma and peripheral blood mononuclear cells (PBMCs).
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30 months
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Intracellular Concentration of Losartan and Antiretrovirals (ARVs)
時間枠:30 months
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Potential Drug-drug Interactions Between Losartan and Antiretrovirals (ARVs) will be assessed by measuring intracellular concentration of losartan and ARVs in lympoidtissue.
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30 months
|
その他の成果指標
結果測定 |
メジャーの説明 |
時間枠 |
---|---|---|
Frequency of Dendritic Cell and CD4 T Cell Interactions With the FRCn
時間枠:30 months
|
As an exploratory endpoint, we will determine the impact of losartan on frequency of dendritic cell and CD4 T cell interactions with the FRCn.
This will be determined using two-photon microscopy in sections on LN obtained from study subjects.
Given that this is an exploratory endpoint, these assays will be performed in a subset of subjects (5 losartan treated, 2 placebo treated and 5 HIV uninfected controls).
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30 months
|
協力者と研究者
スポンサー
捜査官
- 主任研究者:Timothy Schacker, M.D.、University of Minnesota
研究記録日
主要日程の研究
研究開始 (実際)
一次修了 (実際)
研究の完了 (実際)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (見積もり)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
追加の関連 MeSH 用語
その他の研究ID番号
- 1111M06585
- 13-3613 (その他の識別子:Hennepin County Medical Center)
- U01AI105872 (米国 NIH グラント/契約)
この情報は、Web サイト clinicaltrials.gov から変更なしで直接取得したものです。研究の詳細を変更、削除、または更新するリクエストがある場合は、register@clinicaltrials.gov。 までご連絡ください。 clinicaltrials.gov に変更が加えられるとすぐに、ウェブサイトでも自動的に更新されます。
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