Adding Maraviroc to Antiretroviral Therapy for Suboptimal CD4 T-Cell Recovery Despite Sustained Virologic Suppression

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:
NCT00709111
First received: July 1, 2008
Last updated: January 23, 2012
Last verified: January 2012

July 1, 2008
January 23, 2012
January 2009
October 2009   (final data collection date for primary outcome measure)
Change in CD4+ T-cell Count [ Time Frame: From baseline to week 24 ] [ Designated as safety issue: No ]
Change was calculated as the week 24 CD4+ T-cell count (average of the week 22 and week 24 values) minus the baseline CD4+ T-cell count (average of pre-entry and entry values).
Increase in CD4 count [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00709111 on ClinicalTrials.gov Archive Site
  • Proportion of Participants Achieving a 50-cell Increase in CD4+ T-cell Count [ Time Frame: From baseline to week 24 ] [ Designated as safety issue: No ]
    Baseline was defined as the average of pre-entry and entry values. Week 24 was defined as the average of the week 22 and week 24 values.
  • Within-subject CD4+ T-cell Count Slopes [ Time Frame: From baseline through week 24 ] [ Designated as safety issue: No ]
    The estimated mean slope was summarized across the population by using generalized estimating equations. Baseline was defined as the average of pre-entry and entry values. Week 24 was defined as the average of the week 22 and week 24 values.
  • Change From Within-subject Pre-treatment CD4+ T-cell Count Slopes to Corresponding Within-subject CD4+ T-cell Count Slopes From Baseline Through Week 24 [ Time Frame: From pre-treatment through week 24 ] [ Designated as safety issue: No ]
    The estimated mean change in slopes was summarized across the population by using generalized estimating equations. Pre-treatment CD4+ T-cell counts (from at least 48 weeks prior to study entry) were recorded at screening from patient source documentation. Baseline was defined as the average of pre-entry and entry values. Week 24 was defined as the average of the week 22 and week 24 values.
  • Change in CD4+ T-cell Count [ Time Frame: From week 24 to week 36 ] [ Designated as safety issue: No ]
    Change was calculated as week 36 CD4+ T-cell count minus the week 24 CD4+ T-cell count (average of the week 22 and week 24 values).
  • Change in CD4+ T-cell Count [ Time Frame: From week 24 to week 48 ] [ Designated as safety issue: No ]
    Change was calculated as week 48 CD4+ T-cell count (average of week 46 and week 48) minus the week 24 CD4+ T-cell count (average of the week 22 and week 24 values).
  • Change in CD4 Percentage [ Time Frame: From baseline to week 24 ] [ Designated as safety issue: No ]
    Change was calculated as the week 24 CD4 percentage (average of the week 22 and week 24 values) minus the baseline CD4 percentage (average of pre-entry and entry values).
  • Within-subject CD4 Percentage Slopes [ Time Frame: From baseline through week 24 ] [ Designated as safety issue: No ]
    The estimated mean slope was summarized across the population by using generalized estimating equations. Baseline was defined as the average of pre-entry and entry values. Week 24 was defined as the average of the week 22 and week 24 values.
  • Change From Within-subject Pre-treatment CD4 Percentage Slopes to Corresponding Within-subject CD4 Percentage Slopes From Baseline Through Week 24 [ Time Frame: From pre-treatment through week 24 ] [ Designated as safety issue: No ]
    The estimated mean change in slopes was summarized across the population by using generalized estimating equations. Pre-treatment CD4 percentage (from at least 48 weeks prior to study entry) were recorded at screening from patient source documentation. Baseline was defined as the average of pre-entry and entry values. Week 24 was defined as the average of the week 22 and week 24 values.
  • Change in CD4 Percentage [ Time Frame: From week 24 to week 36 ] [ Designated as safety issue: No ]
    Change was calculated as week 36 CD4 percentage minus the week 24 CD4 percentage (average of the week 22 and week 24 values).
  • Change in CD4 Percentage [ Time Frame: From week 24 to week 48 ] [ Designated as safety issue: No ]
    Change was calculated as week 48 CD4 percentage (average of week 46 and week 48) minus the week 24 CD4 percentage (average of the week 22 and week 24 values).
  • Number of Subjects Who Experience a Grade 2, 3 or 4 Signs and Symptoms, Grade 3 or 4 Laboratory Abnormalities, or Death. [ Time Frame: From baseline through week 24 ] [ Designated as safety issue: Yes ]
    Events with date of onset or specimen date prior to first dose of MVC or after the last dose of MVC were excluded. Signs and symptoms with a date of onset the same as the first dose of MVC were excluded if confirmed by the site to be before the first dose. Lab abnormalities with the date of specimen the same as the date of the first dose of MVC were excluded on the assumption that the specimen was drawn before the first dose. Grading used the Division of AIDS (DAIDS) 2004 Severity of Adverse Events Tables, where Grade 1=Mild, 2=Moderate, 3=Severe, 4=Potentially life-threatening.
  • Change in Percentage of CD4+ T-cells That Are: naïve (%CD45RA+CCR7+), Central Memory (%CD45RA-CCR7+), Effector Memory (%CD45RA-CCR7-), Effector (%CD45RA+CCR7-), %HLA-DR+CD38+, %CD38+, %Ki67+, %caspase3+, %Bcl-2-, and %CD57+ [ Time Frame: From baseline to week 24 ] [ Designated as safety issue: No ]
    Change was calculated as the week 24 result (average of the week 22 and week 24 values) minus the baseline result (average of pre-entry and entry values).
  • Change in Percentage of CD8+ T-cells That Are: naïve (%CD45RA+CCR7+), Central Memory (%CD45RA-CCR7+), Effector Memory (%CD45RA-CCR7-), Effector (%CD45RA+CCR7-), %HLA-DR+CD38+, %CD38+, %Ki67+, %caspase3+, %Bcl-2-, and %CD57+ [ Time Frame: From baseline to week 24 ] [ Designated as safety issue: No ]
    Change was calculated as the week 24 result (average of the week 22 and week 24 values) minus the baseline result (average of pre-entry and entry values).
  • Change in Percentage of CD4+ T-cells That Are: naïve (%CD45RA+CCR7+), Central Memory (%CD45RA-CCR7+), Effector Memory (%CD45RA-CCR7-), Effector (%CD45RA+CCR7-), %HLA-DR+CD38+, %CD38+, %Ki67+, %caspase3+, %Bcl-2-, and %CD57+ [ Time Frame: From week 24 to week 36 ] [ Designated as safety issue: No ]
    Change was calculated as week 36 result minus the week 24 result (average of the week 22 and week 24 values).
  • Change in Percentage of CD8+ T-cells That Are: naïve (%CD45RA+CCR7+), Central Memory (%CD45RA-CCR7+), Effector Memory (%CD45RA-CCR7-), Effector (%CD45RA+CCR7-), %HLA-DR+CD38+, %CD38+, %Ki67+, %caspase3+, %Bcl-2-, and %CD57+ [ Time Frame: From week 24 to week 36 ] [ Designated as safety issue: No ]
    Change was calculated as week 36 result minus the week 24 result (average of the week 22 and week 24 values).
  • Change in Percentage of CD4+ T-cells That Are: naïve (%CD45RA+CCR7+), Central Memory (%CD45RA-CCR7+), Effector Memory (%CD45RA-CCR7-), Effector (%CD45RA+CCR7-), %HLA-DR+CD38+, %CD38+, %Ki67+, %caspase3+, %Bcl-2-, and %CD57+ [ Time Frame: From week 24 to week 48 ] [ Designated as safety issue: No ]
    Change was calculated as week 48 result (average of week 46 and week 48) minus the week 24 result (average of the week 22 and week 24 values).
  • Change in Percentage of CD8+ T-cells That Are: naïve (%CD45RA+CCR7+), Central Memory (%CD45RA-CCR7+), Effector Memory (%CD45RA-CCR7-), Effector (%CD45RA+CCR7-), %HLA-DR+CD38+, %CD38+, %Ki67+, %caspase3+, %Bcl-2-, and %CD57+ [ Time Frame: From week 24 to week 48 ] [ Designated as safety issue: No ]
    Change was calculated as week 48 result (average of week 46 and week 48) minus the week 24 result (average of the week 22 and week 24 values).
  • Change in Soluble CD14 [ Time Frame: From baseline to week 24 ] [ Designated as safety issue: No ]
    Change was calculated as the week 24 result (average of the week 22 and week 24 values) minus the baseline result (average of pre-entry and entry values). Soluble CD14 is a marker of gut microbial translocation.
  • Change in Soluble CD14 [ Time Frame: From week 24 to week 36 ] [ Designated as safety issue: No ]
    Change was calculated as week 36 result minus the week 24 result (average of the week 22 and week 24 values). Soluble CD14 is a marker of gut microbial translocation.
  • Change in Soluble CD14 [ Time Frame: From week 24 to week 48 ] [ Designated as safety issue: No ]
    Change was calculated as week 48 result (average of week 46 and week 48) minus the week 24 result (average of the week 22 and week 24 values). Soluble CD14 is a marker of gut microbial translocation.
  • Change in High Sensitivity C-reactive Protein (Hs-CRP) [ Time Frame: From baseline to week 24 ] [ Designated as safety issue: No ]
    Change was calculated as the week 24 result (average of the week 22 and week 24 values) minus the baseline result (average of pre-entry and entry values).
  • Change in Interleukin (IL)-6, Monocyte Chemoattractant Protein (MCP)-1, MCP-2, and Plasma CD40 Ligand (CD40L) [ Time Frame: From baseline to week 24 ] [ Designated as safety issue: No ]
    Change was calculated as the week 24 result (average of the week 22 and week 24 values) minus the baseline result (average of pre-entry and entry values).
  • Change in Intercellular Cell Adhesion Molecule (ICAM)-1, Plasma P-selectin, Soluble TNFRII (sTNFRII), and Matrix Metalloproteinase (MMP)-9 [ Time Frame: From baseline to week 24 ] [ Designated as safety issue: No ]
    Change was calculated as the week 24 result (average of the week 22 and week 24 values) minus the baseline result (average of pre-entry and entry values).
  • Change in D-dimer [ Time Frame: From baseline to week 24 ] [ Designated as safety issue: No ]
    Change was calculated as the week 24 result (average of the week 22 and week 24 values) minus the baseline result (average of pre-entry and entry values).
  • Change in Hs-CRP [ Time Frame: From week 24 to week 36 ] [ Designated as safety issue: No ]
    Change was calculated as week 36 result minus the week 24 result (average of the week 22 and week 24 values).
  • Change in IL-6, MCP-1, MCP-2, and Plasma CD40L [ Time Frame: From week 24 to week 36 ] [ Designated as safety issue: No ]
    Change was calculated as week 36 result minus the week 24 result (average of the week 22 and week 24 values).
  • Change in ICAM-1, Plasma P-selectin, sTNFRII, and MMP-9 [ Time Frame: From week 24 to week 36 ] [ Designated as safety issue: No ]
    Change was calculated as week 36 result minus the week 24 result (average of the week 22 and week 24 values).
  • Change in D-dimer [ Time Frame: From week 24 to week 36 ] [ Designated as safety issue: No ]
    Change was calculated as week 36 result minus the week 24 result (average of the week 22 and week 24 values).
  • Change in Hs-CRP [ Time Frame: From week 24 to week 48 ] [ Designated as safety issue: No ]
    Change was calculated as week 48 result (average of week 46 and week 48) minus the week 24 result (average of the week 22 and week 24 values).
  • Change in IL-6, MCP-1, MCP-2, and Plasma CD40L [ Time Frame: From week 24 to week 48 ] [ Designated as safety issue: No ]
    Change was calculated as week 48 result (average of week 46 and week 48) minus the week 24 result (average of the week 22 and week 24 values).
  • Change in ICAM-1, Plasma P-selectin, sTNFRII, and MMP-9 [ Time Frame: From week 24 to week 48 ] [ Designated as safety issue: No ]
    Change was calculated as week 48 result (average of week 46 and week 48) minus the week 24 result (average of the week 22 and week 24 values).
  • Change in D-dimer [ Time Frame: From week 24 to week 48 ] [ Designated as safety issue: No ]
    Change was calculated as week 48 result (average of week 46 and week 48) minus the week 24 result (average of the week 22 and week 24 values).
  • Proportion of Participants With Detectable HIV-1 Viremia as Measured by Single Copy Assay (SCA) [ Time Frame: At weeks -1 (pre-entry), 0 (entry), 12, 22, 24, and 36 ] [ Designated as safety issue: No ]
    A subject was considered detectable at a specific week if HIV-1 RNA by SCA >=1 copy/ml.
  • Drug Adherence Assessed as Number of Missed Doses Over a 4-day Recall [ Time Frame: At weeks 4, 12, and 24 ] [ Designated as safety issue: No ]
    Self-reported MVC adherence data were based on a four-day (8 expected doses) recall. Based on the wording of the Self Report case report form (CRF), participants reporting that they were currently taking MVC that then failed to complete the record of the number of missed doses were assumed to have no missed doses to report. Missing adherence assessments at a time point of interest were ignored and only those participants completing an adherence assessment at least one time point of interest were included.
  • Persistence of CD4 count increase after discontinuation of MVC [ Time Frame: From Weeks 24 to 48 ] [ Designated as safety issue: No ]
  • Safety and tolerability of MVC in subjects on ART with suboptimal CD4 response [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
  • Mechanism by which MVC influences CD4 count measured by a set of immunologic markers [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • Effect of MVC on gut microbial translocation [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • Effect of MVC on low-level HIV-1 viremia [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • Effect of MVC on inflammatory markers [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • Adherence to study medications and relationship between adherence and study outcome [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Adding Maraviroc to Antiretroviral Therapy for Suboptimal CD4 T-Cell Recovery Despite Sustained Virologic Suppression
A Pilot Trial of Maraviroc for Treatment of Subjects on Antiretroviral Therapy With Suboptimal CD4 T-cell Count Recovery Despite Sustained Virologic Suppression

Despite viral suppression, antiretroviral therapy (ART) does not restore CD4+ T-cell counts in some subjects. The purpose of this study is to assess whether adding maraviroc (MVC) to a suppressive ART will result in a significant CD4+ T-cell count increase over 24 weeks in subjects with suboptimal CD4+ T-cell recovery despite sustained virologic suppression.

The majority of HIV-infected subjects with virologic suppression on antiretroviral therapy (ART) have a marked increase in CD4+ T-cell counts over the first year on treatment. However, a portion of these individuals show a suboptimal immune response and remain at an elevated risk for disease progression. The use of the CCR5 inhibitor maraviroc (MVC) is associated with enhanced CD4+ T-cell recovery in subjects who initiate ART. AIDS Clinical Trials Group (ACTG) A5256 studied the effect of ART intensification with MVC on CD4+ T-cell counts in subjects with suboptimal CD4 recovery despite sustained virologic suppression. Eligible subjects added MVC to their ART regimen, and continued MVC for 24 weeks. At week 24, subjects discontinued MVC and were followed for an additional 24 weeks off MVC.

Subjects were seen through week 48 for clinical and laboratory evaluations, including plasma HIV-1 RNA, CD4+ T-cell count, and safety laboratories. Subjects had 2 baseline visits prior to starting MVC. Study visits were scheduled at weeks 4, 8, 12, 16, 22, 24, 36, 46, and 48. CD4+ T-cell counts were measured at every study visit and HIV-1 RNA at weeks 12, 24, 36, and 48, regardless of treatment status. Measures of activation, T-cell maturation, and apoptosis were performed at all weeks except 4, 8, and 16. At the end of the study, the pre-entry, entry, week 12, 22, 24, and 36 samples for the HIV-1 RNA by single-copy assay (SCA) were run. The week 46 and 48 samples were not run.

Interventional
Not Provided
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
HIV Infections
Drug: Maraviroc
The maraviroc doses were 150 mg orally twice daily, 300 mg orally twice daily, or 600 mg orally twice daily, depending on the pharmacokinetic interaction with a subject's pre-study ART and non-ART drug regimen according to the package insert.
Other Names:
  • MVC
  • Selzentry
Experimental: Maraviroc
Maraviroc (MVC) was taken for 24 weeks, in addition to the subject's current antiretroviral therapy (ART) drug regimen. At week 24, subjects discontinued MVC and were followed for an additional 24 weeks off MVC, but still on current ART drug regimen.
Intervention: Drug: Maraviroc

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
34
April 2010
October 2009   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • HIV-1 infection
  • On ART for at least 48 weeks prior to study entry with a regimen that includes three or more antiretroviral medications
  • No change in ART regimen for at least 24 weeks prior to study entry
  • Screening CD4+ T-cell count less than 250 obtained within 60 days prior to study entry
  • Stable CD4+ T-cell count for at least 48 weeks prior to study entry (as assessed by an estimated CD4+ T-cell count slope between -20 and +20 cells/year)
  • Screening HIV-1 RNA below the limit of detection using an FDA-approved assay obtained within 60 days prior to study entry
  • All other plasma HIV-1 RNA measurements in the 48 weeks prior to study entry must be below the limit of detection
  • Laboratory values obtained within 60 days prior to study entry:

    • Absolute neutrophil count (ANC) >=750/µL
    • Hemoglobin >=9.0 g/dL for female subjects and >=10.0 g/dL for male subjects
    • Platelet count >=50,000/ µL
    • Calculated creatinine clearance (CrCl) >=30 mL/min
    • Aspartate aminotransferase (serum glutamic oxaloacetic transaminase), alanine aminotransferase (serum glutamic pyruvic transaminase), and alkaline phosphatase <=5 X Upper Limit of Normal (ULN)
    • Direct bilirubin <=2.5 X ULN
  • Females of reproductive potential will need a negative serum or urine pregnancy test within 48 hours prior to study entry
  • Agree not to participate in the conception process, and if participating in sexual activity that could lead to pregnancy, the subject/partner must use at least two reliable forms of contraceptives while receiving study treatment and for 6 weeks after stopping study treatment.

Exclusion Criteria:

  • Unstable clinical condition
  • Currently breast-feeding or pregnant
  • Use of immunomodulators or cancer chemotherapy or radiation treatment within 12 months prior to study entry
  • An acute AIDS-defining illness within 60 days prior to study entry
  • Known allergy/sensitivity or hypersensitivity to components of MVC, including allergy or hypersensitivity to soya lecithin, soya or peanuts
  • Active drug or alcohol abuse that, in the opinion of the investigator, would interfere with adherence to study regimens
  • Serious illness requiring systemic treatment and/or hospitalization within 60 days prior to study entry
  • Receipt of a vaccine within 30 days prior to study entry
  • Current or previous use of a CCR5 inhibitor
  • Plan to change background ART regimen within 24 weeks after study entry
  • Receipt of experimental or non-experimental medications for the purpose of raising CD4+ T-cell counts within 6 months prior to study entry
Both
16 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00709111
ACTG A5256, 1U01AI068636
Yes
AIDS Clinical Trials Group
AIDS Clinical Trials Group
National Institute of Allergy and Infectious Diseases (NIAID)
Study Chair: Timothy J. Wilkin, MD, MPH Cornell Clinical Research Site
Study Chair: Roy Gulick, MD, MPH Cornell HIV Clinical Trials Unit
AIDS Clinical Trials Group
January 2012

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