Chloroquine for Reducing Immune Activation in HIV- Infected Individuals

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:
NCT00819390
First received: January 8, 2009
Last updated: July 29, 2014
Last verified: July 2014
  Purpose

HIV is characterized by frequent immune system activation. Early in the course of infection the body establishes an immune activation "set point" related to the amount of HIV in the blood stream. This set point affects the rate of CD4 cell loss. Without CD4 cells, or with very low levels of CD4 cells, the body cannot fight off illness. This is known as immunodeficiency. If left untreated HIV can lead to extreme immunodeficiency and AIDS.

Evidence suggests that by decreasing the rate of immune system activation, immune deficiency progression could be prevented. The purpose of this study is to learn how well chloroquine can reduce the level of immune activation and to test the safety and tolerance of chloroquine in people infected with HIV.


Condition Intervention Phase
HIV Infections
Drug: Chloroquine
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver)
Primary Purpose: Treatment
Official Title: A Phase II, Double Blind, Randomized, Exploratory Study of Chloroquine for Reducing HIV-Associated Immune Activation

Resource links provided by NLM:


Further study details as provided by AIDS Clinical Trials Group:

Primary Outcome Measures:
  • Number of CD38 molecules per cell on CD8 T lymphocytes minus the number of CD38 molecules per cell on CD8 T lymphocytes at baseline [ Time Frame: At Baseline and Week 10 or Week 12 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Number of CD38 molecules per cell on CD8 T lymphocytes at the end of the 12-week period in the given arm when chloroquine treatment is given minus the number of CD38 molecules per cell on CD8 T lymphocytes at the beginning of that same period [ Time Frame: Before and after start of treatment ] [ Designated as safety issue: No ]
  • Occurrence of a Grade 3 or higher event [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
  • RNA copies/mL at study entry and study Weeks 12 and 24 [ Time Frame: At Entry and at Weeks 12 and 24 ] [ Designated as safety issue: No ]
  • Number of CD38 molecules per CD8 T lymphocytes at Week 24 minus the number of CD38 molecules per cell on CD8 T lymphocytes at study entry in Arm A [ Time Frame: At Entry and Week 24 ] [ Designated as safety issue: No ]
  • Total CD4 T cell count at Week 12 minus total CD4 T cell count at study entry [ Time Frame: At Entry and Week 12 ] [ Designated as safety issue: No ]
  • Number of CD38 molecules per CD8 T lymphocytes at Week 24 minus the number of CD38 molecules per cell on CD8 T lymphocytes at Week 12 in Arm A [ Time Frame: At Weeks 12 and 24 ] [ Designated as safety issue: No ]
  • Proportion of CD3 CD8 T cells that express CD38 [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • Proportion of CD3 CD8 T cells that express CD38 and human leukocyte antigen (HLA) DR [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • Proportion of CD3 CD4 T cells that express CD38 and HLA DR [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • Bacterial 16s rDNA levels expressed as copies/mm^3 of plasma [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • The number of CD38 molecules per cell on CD8 T lymphocytes at Week 28 minus the number of Cd38 molecules per cell on CD8 T lymphocytes at the latest evaluation prior to receiving active chloroquine [ Time Frame: At Week 28 and most prior evaluation ] [ Designated as safety issue: No ]
  • Fasting lipopolysaccharide LPS and bacterial 16s rDNA levels [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • Activation levels of pDC and mDC [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • The profile of gene expression in white blood cells at scheduled timepoints [ Time Frame: Throughout study ] [ Designated as safety issue: No ]

Enrollment: 70
Study Start Date: March 2009
Study Completion Date: May 2013
Primary Completion Date: February 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Participants will receive chloroquine from Day 0 through the Week 12 study visit. Participants will then change to placebo treatment until the Week 24 study visit.
Drug: Chloroquine
Taken orally, once daily, at a dose of 250 mg for 12 weeks.
Drug: Placebo
Taken orally, once daily for 12 weeks.
Experimental: 2
Participants will receive a chloroquine placebo treatment from Day 0 through the Week 12 study visit. Participants will then begin treatment with chloroquine until the Week 24 study visit.
Drug: Chloroquine
Taken orally, once daily, at a dose of 250 mg for 12 weeks.
Drug: Placebo
Taken orally, once daily for 12 weeks.

Detailed Description:

HIV is characterized by persistent immune system activation, and early in the course of infection the body establishes an immune activation "set point" related to the amount of HIV in the blood stream. This set point affects the rate of CD4 cell loss. Without CD4 cells, or with very low levels of CD4 cells, the body cannot fight off illness. This is known as immunodeficiency. If left untreated HIV can lead to extreme immunodeficiency and AIDS.

Immune system activation includes activating the CD8 cells. These cells attack body cells infected with viruses. Because of this, CD4 cells infected with HIV are frequently destroyed by CD8 cells. The purpose of this study is to learn how well chloroquine reduces the level of activation of CD8 cells in people infected with HIV. Increased activation of CD8 cells is thought to lead to a more severe path of disease in HIV infection.

The constant immune activation observed in HIV- infected patients has also been linked to higher levels of byproducts from certain naturally occurring bacteria found in the gut that are known to be immune stimulants. By decreasing the stimulation from these byproducts with chloroquine treatment, HIV disease may be slowed.

The purpose of this study is to learn how well chloroquine reduces the level of activation of CD8 cells and lowers the levels of bacteria byproducts in people infected with HIV. This study will also look at how well chloroquine is tolerated and its safety in HIV- infected patients.

Participants in this study will be randomly assigned to one of two treatment arms:

Arm A: Participants will receive 12 weeks of chloroquine treatment followed by 12 weeks of placebo

Arm B: Participants will receive 12 weeks of placebo followed by 12 weeks of chloroquine

Study treatment will be given once a day for a full 24 weeks. There will be an additional 4 weeks of follow-up for purposes of safety. After treatment has started, participants will be asked to come to the clinic on Weeks 4, 10, 12, 16, 22, and 24. At each visit participants will receive enough study treatment to last until the next visit. Each visit will last between 30 and 60 minutes. At most visits participants will have a physical exam, answer questions about any medications they are taking and how they are feeling, and have blood drawn for safety to assess CD4/CD8 cell counts and viral load. Some additional blood will also be stored for immunology testing. At some visits participants will be asked questions about their medication and medical history, have pupils dilated, have a hearing test, and have an electrocardiogram (EKG). Some visits will require participants to arrive fasting. Pregnancy tests may also be conducted if the participant is able to become pregnant or if pregnancy is suspected.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • HIV infected
  • No antiretroviral therapy (ART) for at least 6 months prior to study entry and not likely to start within the 6 months after study entry
  • CD4 count greater than or equal to 400 cells/mm3 at screening, obtained within 30 days prior to study entry
  • For participants with previous ART use, documentation or recall of nadir CD4 cell count greater than or equal to 200 cells/mm3
  • Viral load greater than or equal to 1,000 copies/mL obtained within 30 days prior to study entry
  • Certain specified laboratory values obtained within 30 days prior to study entry. More information on this criterion can be found in the study protocol.
  • Documentation that pre-entry specimen for the primary immune activation endpoint responses has been obtained
  • Female participants of reproductive potential must have a negative pregnancy test performed within 24 hours prior to study entry
  • If engaging in sexual activity, female participants must use adequate forms of contraception while receiving study treatment and for 4 weeks after stopping the treatment. More information on this criterion can be found in the study protocol.
  • No history of CDC category C AIDS-related opportunistic infections
  • Karnofsky performance score greater than or equal to 70 within 30 days prior to study entry
  • Ability and willingness to provide informed consent

Exclusion Criteria:

  • Continuous use of certain specified medication for more than 3 days within 30 days prior to study entry. More information on this criterion can be found in the study protocol.
  • Use of chloroquine or hydroxychloroquine within 3 months prior to study entry
  • Known history of hypersensitivity to 4-aminoquinoline compounds (such as chloroquine or hydroxychloroquine)
  • Active drug or alcohol use or dependence that, in the opinion of the investigator would interfere with adherence to study requirements
  • Serious illness requiring systemic treatment and/or hospitalization within 30 days prior to study entry
  • Renal insufficiency, defined as serum creatinine greater than 1.5 mg/L, within 30 days prior to study entry
  • History of retinal disease
  • History of neoplasm other than localized squamous cell carcinoma of the skin
  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency at screening
  • History of porphyria
  • History of psoriasis
  • History of cirrhosis
  • History of seizure disorder
  • A hearing threshold more than 25 decibels at any frequency from 500 hertz up to 2,000 hertz or more than 40 decibels at any frequency from 3,000 hertz up to and including 4,000 hertz on screening pure-tone audiogram by air conduction testing
  • History of tinnitus or history of sudden hearing loss
  • History of myopathy
  • History of cardiac conduction abnormality or cardiomyopathy. More information on this criterion can be found in the study protocol.
  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: NCT00819390

Locations
United States, Alabama
Alabama Therapeutics CRS (5801)
Birmingham, Alabama, United States, 35294
United States, California
Ucsd, Avrc Crs (701)
San Diego, California, United States, 92103
United States, Colorado
University of Colorado Hospital CRS (6101)
Aurora, Colorado, United States, 80045
United States, District of Columbia
Georgetown University CRS (GU CRS) (1008)
Washington, District of Columbia, United States, 20007
United States, Maryland
Johns Hopkins Adult AIDS CRS (201)
Baltimore, Maryland, United States, 21205
United States, Massachusetts
Massachusetts General Hospital ACTG CRS (101)
Boston, Massachusetts, United States, 02114
United States, Missouri
Washington University CRS (2101)
St. Louis, Missouri, United States, 63110
United States, New York
Cornell CRS (7804)
New York, New York, United States, 10011
United States, North Carolina
Unc Aids Crs (3201)
Chapel Hill, North Carolina, United States, 27514
United States, Ohio
Univ. of Cincinnati CRS (2401)
Cincinnati, Ohio, United States, 45267
Case CRS (2501)
Cleveland, Ohio, United States, 44106
MetroHealth CRS (2503)
Cleveland, Ohio, United States, 44109
United States, Pennsylvania
Hosp. of the Univ. of Pennsylvania CRS (6201)
Philadelphia, Pennsylvania, United States, 19104
Pittsburgh CRS (1001)
Pittsburgh, Pennsylvania, United States, 15213
United States, Tennessee
Vanderbilt Therapeutics CRS (3652)
Nashville, Tennessee, United States, 37204
Sponsors and Collaborators
AIDS Clinical Trials Group
Investigators
Study Chair: Jeffrey M Jacobson, MD Drexel University College of Medicine
  More Information

Additional Information:
Publications:
Responsible Party: AIDS Clinical Trials Group
ClinicalTrials.gov Identifier: NCT00819390     History of Changes
Other Study ID Numbers: ACTG A5258, 1U01AI068636
Study First Received: January 8, 2009
Last Updated: July 29, 2014
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
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
Chloroquine
Chloroquine diphosphate
Amebicides
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antimalarials
Antirheumatic Agents
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Filaricides
Antinematodal Agents

ClinicalTrials.gov processed this record on August 20, 2014