Clinical trial NCT00819390: Chloroquine for Reducing Immune Activation in HIV- Infected Individuals
Official title: A Phase II, Double Blind, Randomized, Exploratory Study of Chloroquine for Reducing HIV-Associated Immune Activation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2009-01-09
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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.

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 was 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, either off antiretroviral therapy (ART) (protocol version 1.0 dated December 17, 2008) or on-ART (protocol version 2.0 dated October 1, 2010). The off-ART (Arms A and B) and on-ART (Arms C and D) participants were enrolled during different time periods, and the study was designed to analyze the two study populations separately. This study also looked at how well chloroquine was tolerated and its safety in HIV- infected participants.

Off-ART participants in the study were randomized with equal probability to one of two treatment arms:

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

Arm B: Participants received 12 weeks of placebo followed by 12 weeks of chloroquine

On-ART participants in the study were randomized with equal probability to one of two treatment arms:

Arm C: Participants received 12 weeks of chloroquine treatment followed by 12 weeks of placebo

Arm D: Participants received 12 weeks of placebo followed by 12 weeks of chloroquine

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

Eligibility criteria: Inclusion Criteria:

* HIV-1 infected
* 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.
* Ability and willingness to provide informed consent

Additional Inclusion Criteria for Off-ART Participants:

* 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 cell 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
* HIV-1 RNA viral load greater than or equal to 1,000 copies/mL obtained within 30 days prior to study entry
* 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

Additional Inclusion Criteria for On-ART Participants:

* Receiving ART, defined as a regimen that includes three or more antiretroviral medications, for at least 24 months prior to study entry
* Required documentation that all HIV-1 viral loads (at least two) were below 400 copies/mL. More information on this criterion can be found in the study protocol.
* Screening HIV-1 RNA \<200 copies/mL within 30 days prior to study entry. More information on this criterion can be found in the study protocol.
* CD4 cell count \<350 cells/mm3 at screening, obtained within 30 days prior to study entry

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/dL, within 30 days prior to study entry
* History of retinal disease (i.e. confirmed retinopathy by ophthalmologic examination)
* History of neoplasm, within 5 years prior to study entry, other than treated in situ carcinoma or basal-cell or 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
* History of tinnitus (ear and/or head noise lasting more than 5 minutes that occurs more often than once per week) 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.

Additional Exclusion Criteria for On-ART Participants:

- Plans to change ART regimen with the 6 months after study entry (change in ART regimen is only permitted if due to toxicity)

Primary outcomes:
measure: Change in Percent CD8 HLA-DR+/CD38+ From Baseline to Week 12
timeFrame: At pre-entry, entry, weeks 10 and 12
Secondary outcomes:
measure: Change in Percent CD8 HLA-DR+/CD38+ From Start to End of the 12-week Chloroquine Treatment Period
timeFrame: For Arms A and C: Pre-entry, entry, weeks 10 and 12. For Arms B and D: Weeks 10, 12, 22 and 24
measure: Change in Percent CD8 HLA-DR+/CD38+ From Week 12 to Week 24
timeFrame: At Weeks 10, 12, 22 and 24
measure: Change in Percent CD8 HLA-DR+/CD38+ From Baseline to Week 24 in Arm A and Arm C
timeFrame: At Pre-entry, entry, Weeks 22 and 24
measure: Change in Total CD4 T Cell Count From Baseline to Week 12
timeFrame: At pre-entry, entry, weeks 10 and 12
measure: Number of Participants With Events Grade 3 or Higher
timeFrame: From start of study treatment to study completion at week 28
measure: HIV-1 RNA Copies/mL at Study Entry for Off-ART Participants
timeFrame: At Entry
measure: HIV-1 RNA Copies/mL at Weeks 12 and 24 for Off-ART Participants
timeFrame: At weeks 12 and 24
measure: HIV-1 RNA Copies/mL at Study Entry for On-ART Participants
timeFrame: At Entry
measure: HIV-1 RNA Copies/mL at Week 12 for On-ART Participants
timeFrame: At week 12
measure: HIV-1 RNA Copies/mL at Week 24 for On-ART Participants
timeFrame: At week 24
measure: Percent CD8 CD38+ at Baseline
timeFrame: At pre-entry and entry
measure: Percent CD8 CD38+ at Week 12
timeFrame: At Week 12
measure: Percent CD8 CD38+ at Week 24
timeFrame: At Week 24
measure: Percent CD4 HLA-DR+/CD38+ at Baseline
timeFrame: At pre-entry and entry
measure: Percent CD4 HLA-DR+/CD38+ at Week 12
timeFrame: At Week 12
measure: Percent CD4 HLA-DR+/CD38+ at Week 24
timeFrame: At Week 24
measure: IL-6, Soluble TNF-rI (sTNF-rI) and D-dimer at Baseline
timeFrame: At pre-entry and entry
measure: IL-6, Soluble TNF-rI (sTNF-rI) and D-dimer at Week 12
timeFrame: At week 12
measure: IL-6, Soluble TNF-rI (sTNF-rI) and D-dimer at Week 24
timeFrame: At week 24
measure: Soluble CD14 (sCD14) at Baseline
timeFrame: At pre-entry and entry
measure: Soluble CD14 (sCD14) at Week 12
timeFrame: At week 12
measure: Soluble CD14 (sCD14) at Week 24
timeFrame: At week 24
measure: Fasting Lipopolysaccharides (LPS) at Entry
timeFrame: At entry
measure: Fasting Lipopolysaccharides (LPS) at Week 12
timeFrame: At week 12
measure: Fasting Lipopolysaccharides (LPS) at Week 24
timeFrame: At week 24
measure: Percent Activation Levels of Plasmacytoid Dendritic Cells (pDC) and Myeloid Dendritic Cells (mDC) at Baseline
timeFrame: At pre-entry and entry
measure: Percent Activation Levels of Plasmacytoid Dendritic Cells (pDC) and Myeloid Dendritic Cells (mDC) at Week 12
timeFrame: At week 12
measure: Percent Activation Levels of Plasmacytoid Dendritic Cells (pDC) and Myeloid Dendritic Cells (mDC) at Week 24
timeFrame: At week 24
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama Therapeutics CRS (5801)
state: Alabama
city: San Diego
country: United States
facility: Ucsd, Avrc Crs (701)
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS (6101)
state: Colorado
city: Washington
country: United States
facility: Georgetown University CRS (GU CRS) (1008)
state: District of Columbia
city: Baltimore
country: United States
facility: Johns Hopkins Adult AIDS CRS (201)
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital ACTG CRS (101)
state: Massachusetts
city: St. Louis
country: United States
facility: Washington University CRS (2101)
state: Missouri
city: New York
country: United States
facility: Cornell CRS (7804)
state: New York
city: Chapel Hill
country: United States
facility: Unc Aids Crs (3201)
state: North Carolina
city: Cincinnati
country: United States
facility: Univ. of Cincinnati CRS (2401)
state: Ohio
city: Cleveland
country: United States
facility: Case CRS (2501)
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth CRS (2503)
state: Ohio
city: Philadelphia
country: United States
facility: Hosp. of the Univ. of Pennsylvania CRS (6201)
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Pittsburgh CRS (1001)
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt Therapeutics CRS (3652)
state: Tennessee
Study officials:
affiliation: Drexel University College of Medicine
name: Jeffrey M Jacobson, MD
role: STUDY_CHAIR
References:
citation: Neely M, Kalyesubula I, Bagenda D, Myers C, Olness K. Effect of chloroquine on human immunodeficiency virus (HIV) vertical transmission. Afr Health Sci. 2003 Aug;3(2):61-7.
citation: Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: an old drug against today's diseases? Lancet Infect Dis. 2003 Nov;3(11):722-7. doi: 10.1016/s1473-3099(03)00806-5.
citation: Semrau K, Kuhn L, Kasonde P, Sinkala M, Kankasa C, Shutes E, Vwalika C, Ghosh M, Aldrovandi G, Thea DM. Impact of chloroquine on viral load in breast milk. Trop Med Int Health. 2006 Jun;11(6):800-3. doi: 10.1111/j.1365-3156.2006.01645.x.
citation: Jacobson JM, Bosinger SE, Kang M, Belaunzaran-Zamudio P, Matining RM, Wilson CC, Flexner C, Clagett B, Plants J, Read S, Purdue L, Myers L, Boone L, Tebas P, Kumar P, Clifford D, Douek D, Silvestri G, Landay AL, Lederman MM. The Effect of Chloroquine on Immune Activation and Interferon Signatures Associated with HIV-1. AIDS Res Hum Retroviruses. 2016 Jul;32(7):636-47. doi: 10.1089/AID.2015.0336. Epub 2016 Apr 19.