Reversing Tissue Fibrosis to Improve Immune Reconstitution in HIV

NCT ID: NCT01852942

Last Updated: 2020-12-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 52 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-09-30
• Study Completion Date: 2019-07-16

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. 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.

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).

Conditions

HIV Infection; HIV Infections

Keywords

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Losartan

Group Type: EXPERIMENTAL

Losartan

Intervention Type: 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.

Sugar Pill

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

one tablet by mouth daily

Interventions

Losartan

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.

Intervention Type: DRUG

Placebo

one tablet by mouth daily

Intervention Type: DRUG

Other Intervention Names

Cozaar

Eligibility Criteria

Inclusion Criteria

• 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.

• HIV uninfected.

-≥ 18 years of age.

• No contraindication to proposed study procedures.

Exclusion Criteria

• 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:

• 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: collaborator

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

University of Minnesota

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Timothy Schacker, M.D.

Role: PRINCIPAL_INVESTIGATOR

University of Minnesota

Locations

University of Minnesota, Division of Infectious Diseases

Minneapolis, Minnesota, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

13-3613

Identifier Type: OTHER

Identifier Source: secondary_id

U01AI105872

Identifier Type: NIH

Identifier Source: secondary_id

View Link

1111M06585

Identifier Type: -

Identifier Source: org_study_id