Reversing Tissue Fibrosis to Improve Immune Reconstitution in HIV

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by University of Minnesota - Clinical and Translational Science Institute
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier:
NCT01852942
First received: February 20, 2012
Last updated: September 5, 2014
Last verified: September 2014
  Purpose

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:

  1. reverse existing lymphoid tissue fibrosis,
  2. restore lymphoid tissue architecture,
  3. increase the number and improve the function of peripheral and lymphatic CD4 T cells,
  4. decrease levels of systemic immune activation (IA),
  5. decrease size of the HIV reservoir, and
  6. be safe and well tolerated.

Condition Intervention Phase
HIV Infection
HIV Infections
Drug: Losartan
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Reversing Tissue Fibrosis to Improve Immune Reconstitution in HIV

Resource links provided by NLM:


Further study details as provided by University of Minnesota - Clinical and Translational Science Institute:

Primary Outcome Measures:
  • The primary endpoint is to determine the impact of losartan treatment on lymphoid tissue (LT) fibrosis. [ Time Frame: 30 months ] [ Designated as safety issue: No ]
    This will be determined by measuring the amount of collagen deposition in LT and the integrity of the FRCn using immunohistochemistry (IHC) and quantitative image analysis (QIA). LT will be obtained at baseline, month 12 and month 30.


Secondary Outcome Measures:
  • We will assess the impact of losartan on immune reconstitution and function. [ Time Frame: 30 months ] [ Designated as safety issue: No ]

    This will be determined by measuring:

    1. Frequency of CD4+ T cells, TUNEL+CD3+CD8+ T cells and cells expressing TGF-beta and lymphotoxin-beta in LT using IHC.
    2. Serum levels of IL-7 and TGF-beta using ELISA.
    3. The immune response to HPV vaccination using flow cytometry to identify cells stimulated by specific HPV peptides.

  • We will determine the impact of losartan on immune activation in HIV infected, treated individuals. [ Time Frame: 30 months ] [ Designated as safety issue: No ]

    This will be determined by measuring:

    1. 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.
    2. Percentage of activated T cells, macrophages and dendritic cells in PBMCs and LT using flow cytometry.
    3. Intracellular levels of the inflammatory cytokines IL-17, IFNg, IL-2, TNF, IL-10, and GM-CSF in PBMCs and LT using cytokine staining.
    4. Plasma levels of additional inflammatory markers including LPS, sCD14, I-FABP, IL-1b, IL-1RA, IL-6, TNF, amyloid A, CRP, and D-dimer using limulus assay (sCD14) and ELISA (all others).

  • We will assess the potential for losartan to reduce the size of the viral reservoir. [ Time Frame: 30 months ] [ Designated as safety issue: No ]
    This will be assessed by determining the frequency of HIV RNA+ and DNA+ cells in LN and GALT using both radiolabeled in situ hybridization (ISH) and RNAscopeTM in situ technology.

  • We will assess for any potential drug-drug interactions between losartan and antiretrovirals (ARVs). [ Time Frame: 30 months ] [ Designated as safety issue: Yes ]

    This will be determined by:

    1. Performing an intensive pharmacokinetics experiment in all HIV infected subjects at month 1 of the study (when losartan is at steady state).
    2. Measuring levels of ARVs and losartan in plasma and peripheral blood mononuclear cells (PBMCs) quarterly over the 30-month study period.
    3. Measuring intracellular levels of losartan and ARVs in LT at month 30.


Other Outcome Measures:
  • As an exploratory endpoint, we will determine the impact of losartan on frequency of dendritic cell and CD4 T cell interactions with the FRCn. [ Time Frame: 30 months ] [ Designated as safety issue: No ]
    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).


Estimated Enrollment: 57
Study Start Date: September 2014
Estimated Study Completion Date: July 2018
Estimated Primary Completion Date: July 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Losartan Drug: Losartan
We will start with 50 mg of losartan by mouth daily. We will increase the dosage 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.
Other Name: Cozaar
Placebo Comparator: Sugar Pill Drug: Placebo
one tablet by mouth daily

Detailed Description:

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).

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

HIV infected participants:

  1. 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.
  2. 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:

  1. 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.
  2. 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01852942

Contacts
Contact: Ann Thorkelson, RN 612-625-7472 segu0017@umn.edu

Locations
United States, Minnesota
University of Minnesota, Division of Infectious Diseases Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Ann Thorkelson, RN    612-625-7472    segu0017@umn.edu   
Principal Investigator: Timothy Schacker, M.D.         
Sub-Investigator: Gregory Beilman, M.D.         
Sub-Investigator: Cavan Reilly, Ph.D.         
Sub-Investigator: Jeffrey Chipman, MD         
Sub-Investigator: Jason Baker, MD         
Sub-Investigator: Brian Fife, PhD         
Sub-Investigator: Courtney Fletcher, PharmD         
Sub-Investigator: Daniel Douek, MD, PhD         
Sub-Investigator: Richard Koup, MD         
Sub-Investigator: Jacob Estes, PhD         
Sponsors and Collaborators
University of Minnesota - Clinical and Translational Science Institute
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Timothy Schacker, M.D. University of Minnesota - Clinical and Translational Science Institute
  More Information

No publications provided

Responsible Party: University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier: NCT01852942     History of Changes
Other Study ID Numbers: 1111M06585, 13-3613, U01AI105872
Study First Received: February 20, 2012
Last Updated: September 5, 2014
Health Authority: United States: Institutional Review Board
United States: Data and Safety Monitoring Board
United States: Federal Government

Keywords provided by University of Minnesota - Clinical and Translational Science Institute:
Infection
HIV 1
HIV
Losartan
Fibrosis
Immune Activation
Immune Reconstitution

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Fibrosis
Infection
Communicable Diseases
Pathologic Processes
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Losartan
Anti-Arrhythmia Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 22, 2014