Reversing Tissue Fibrosis to Improve Immune Reconstitution in HIV

NCT01852942 | Completed Phase 2 Results DMC

• 3 other identifiers: 1111M0658513-3613U01AI105872
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

HIV Infection; HIV Infections

Keywords

Infection; HIV 1; HIV; Losartan; Fibrosis; Immune Activation; Immune Reconstitution

Outcome Measures

Primary Outcomes (2)

• Collagen Deposition in LT

  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.

  30 months

• Integrity of the Fibroblastic Reticular Cell Network (FRCn)

  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.

  30 months

Secondary Outcomes (41)

• Frequency of CD4+ T Cells

  30 months

• Frequency TUNEL+CD3+CD8+ T Cells

  30 months

• Frequency of Cells Expressing TGF-beta and Lymphotoxin-beta

  30 months

• Serum Concentration of IL-7

  30 months

• Serum Concentration of TGF-beta

  30 months

Other Outcomes (1)

• Frequency of Dendritic Cell and CD4 T Cell Interactions With the FRCn

  30 months

Study Arms (2)

Losartan

EXPERIMENTAL

Drug: Losartan

Sugar Pill

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Losartan DRUG

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.

Also known as: Cozaar

Losartan

Placebo DRUG

one tablet by mouth daily

Sugar Pill

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Minnesota: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

University of Minnesota, Division of Infectious Diseases

Minneapolis, Minnesota, 55455, United States

Location

MeSH Terms

Conditions

HIV Infections; Infections; Fibrosis

Interventions

Losartan

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; 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; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Tetrazoles

Results Point of Contact

• Title: Timothy Schacker, MD
• Organization: University of Minnesota

olso7966@umn.edu

612-626-6577

Study Officials

• Timothy Schacker, M.D.

  University of Minnesota

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

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: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 20, 2012
• First Posted: May 14, 2013
• Study Start: September 1, 2014
• Primary Completion: July 16, 2019
• Study Completion: July 16, 2019
• Last Updated: December 11, 2020
• Results First Posted: December 11, 2020

Record last verified: 2020-11

Locations

US (1)