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Maraviroc as an Immunomodulatory Drug for Antiretroviral-treated HIV Infected Patients Exhibiting Immunologic Failure

This study has been completed.
Sponsor:
Collaborators:
Pfizer
amfAR, The Foundation for AIDS Research
Stanford University
Case Western Reserve University
Rush University
Information provided by (Responsible Party):
University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT00735072
First received: August 12, 2008
Last updated: June 13, 2012
Last verified: June 2012

August 12, 2008
June 13, 2012
September 2008
April 2010   (final data collection date for primary outcome measure)
Week 24 Change in Percentage of CD8+ T Cells That Co-express CD38 and HLA DR (Week 24 %CD38+HLA-DR+ CD8+ T Cells Minus Baseline %CD38+HLA-DR+ CD8+ T Cells) [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
Change in % CD38+ HLA-DR+ CD8+ T cells [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00735072 on ClinicalTrials.gov Archive Site
  • Change in CD4+ T Cell Count [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
  • Change in Ultra-sensitive Plasma HIV RNA Level (Single Copy/ml Assay) [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
  • Change in Brachial Artery Flow-mediated Dilatation (UCSF Site Only) [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
  • Change in Gut-associated Lymphoid Tissue HIV RNA Level (UCSF Site Only) [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
Same as current
Not Provided
Not Provided
 
Maraviroc as an Immunomodulatory Drug for Antiretroviral-treated HIV Infected Patients Exhibiting Immunologic Failure
Maraviroc as an Immunomodulatory Drug for Antiretroviral-treated HIV Infected Patients Exhibiting Immunologic Failure

Many people with HIV fail to regain normal CD4 counts despite effectively suppressing HIV replication with medications. Blocking the "co-receptor" for HIV might decrease inflammation of the immune system, potentially providing an immune benefit. The goal of the current trial is to determine whether adding maraviroc, a new CCR5 "co-receptor" blocker, decreases inflammation, providing an immune benefit for patients with low CD4 counts despite undetectable viral loads on HIV medications.

In this study, HIV-infected patients who are receiving antiretroviral therapy for HIV will receive either maraviroc or a placebo (sugar pill) each day for 24 weeks. After 24 weeks, the study medication will be stopped and all subjects will be followed for 12 more weeks. Blood tests measuring the extent of inflammation, low-level viremia, and immune function will be measured throughout the trial and compared between treatment arms.

Our primary hypothesis is that CCR5 inhibitors may have protective immunomodulatory effects independent of their impact on HIV replication. Specifically, we predict that maraviroc will reduce the persistent T cell activation that prevents normal immune reconstitution during HAART-mediated viral suppression. This hypothesis will be tested in the context of a placebo controlled pilot study assessing the impact of maraviroc in antiretroviral-treated patients with a CD4+ T cell count less than 350 cells/mm3. In order to address the immunologic activity of this drug independent of plasma HIV RNA levels, we will study individuals who have undetectable viral loads (< 75 copies RNA/mL). Subjects will be randomized to maraviroc for 24 weeks or matching placebo for 24 weeks, followed by a 12 week washout period. We will use as our primary endpoint the proportion of CD8+ T cells that co-expresses CD38 and HLA-DR, as these outcomes have been well validated in prior studies. The primary outcome will be change in the percentage of activated CD8+ T cells at week 24. Change in CD4+ T cell counts, HIV RNA levels (using ultra-sensitive techniques), and other more experimental immunologic measurements will be assessed as secondary outcomes.

Interventional
Phase 4
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
HIV Infection
  • Drug: Placebo
    Dose based on current medications in regimen: 150mg PO BID for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens.
    Other Name: Placebo for Maraviroc
  • Drug: Maraviroc
    Dose based on current medications in regimen: 150mg orally (PO) twice daily (BID) for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens.
    Other Name: Selzentry
  • Experimental: Maraviroc
    Maraviroc (dose based on current medications in regimen: 150mg orally (PO) twice daily (BID) for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens).
    Intervention: Drug: Maraviroc
  • Placebo Comparator: Placebo
    Placebo (dose based on current medications in regimen: 150mg PO BID for those on a protease inhibitor-based regimen other than Tipranavir; 600mg PO BID for efavirenz-containing regimens; or 300 mg PO BID for all other regimens).
    Intervention: Drug: Placebo
Hunt PW, Shulman NS, Hayes TL, Dahl V, Somsouk M, Funderburg NT, McLaughlin B, Landay AL, Adeyemi O, Gilman LE, Clagett B, Rodriguez B, Martin JN, Schacker TW, Shacklett BL, Palmer S, Lederman MM, Deeks SG. The immunologic effects of maraviroc intensification in treated HIV-infected individuals with incomplete CD4+ T-cell recovery: a randomized trial. Blood. 2013 Jun 6;121(23):4635-46. doi: 10.1182/blood-2012-06-436345. Epub 2013 Apr 15.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
45
July 2010
April 2010   (final data collection date for primary outcome measure)

Inclusion Criteria:

  1. HIV-1 infection, as documented by any licensed ELISA test kit and confirmed by Western blot at any time prior to study entry. HIV-1 culture, HIV-1 antigen, plasma HIV-1 RNA, or a second antibody test by a method other than ELISA is acceptable as an alternative confirmatory test.
  2. Stable antiretroviral therapy for at least 12 months
  3. Screening CD4+ T cell count below 350 cells/mm3
  4. All available CD4+ T cell counts in the last year and at screening < 350 cells/mm3
  5. Screening plasma HIV RNA levels below level of detection (< 50 copies RNA/mL using Roche Amplicor or < 75 copies/mL using Bayer bDNA)
  6. All available plasma HIV RNA levels within past year below the level of detection. Isolated values that are detectable but < 500 copies will be allowed as long as the plasma HIV RNA levels before and after this time point are undetectable.
  7. > 90% adherence to therapy within the preceding 30 days, as determined by self-report.
  8. Both male and female subjects are eligible. Females of childbearing potential must have a negative serum pregnancy test at screening and agree to use a double-barrier method of contraception throughout the study period.
  9. Ability and willingness of subject or legal guardian/representative to provide informed consent

Exclusion Criteria:

  1. Increase in CD4 count of > 100 cells/mm3 in past year.
  2. Patients who are intending to modify antiretroviral therapy in the next 24 weeks for any reason.
  3. Serious illness requiring hospitalization or parental antibiotics within preceding 3 months.
  4. Concurrent treatment with immunomodulatory drugs, or exposure to any immunomodulatory drug in past 16 weeks.
  5. HBVsAg+ or active hepatitis C or hepatitis B which will require treatment in the subsequent 24 weeks.
  6. Prior exposure to CCR5 inhibitors
  7. Screening absolute neutrophil count <1,000 cells/mm3, platelet count <50,000 cells/mm3, hemoglobin < 8mg/dL, estimated creatinine clearance <40 mL/minute.
  8. Pregnant or breastfeeding women
  9. Use of both Tenofovir and Didanosine in current antiretroviral therapy regimen.
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00735072
GA9001DE
Yes
University of California, San Francisco
University of California, San Francisco
  • Pfizer
  • amfAR, The Foundation for AIDS Research
  • Stanford University
  • Case Western Reserve University
  • Rush University
Principal Investigator: Peter W Hunt, MD University of California, San Francisco
Principal Investigator: Steven G Deeks, MD University of California, San Francisco
Principal Investigator: Nancy Shulman, MD Stanford University
Principal Investigator: Robert Shafer, MD Stanford University
Principal Investigator: Michael Lederman, MD Case Western Reserve University
Principal Investigator: Toyin Adeyemi, MD Rush University
University of California, San Francisco
June 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP