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Trial of Maraviroc (UK-427,857) in Combination With Optimized Background Therapy Versus Optimized Background Therapy Alone for the Treatment of Antiretroviral-Experienced NonCCR5-Tropic HIV-1 Infected Subjects

This study has been completed.
Sponsor:
Collaborator:
Pfizer
Information provided by:
ViiV Healthcare
ClinicalTrials.gov Identifier:
NCT00098748
First received: December 7, 2004
Last updated: November 19, 2010
Last verified: November 2010
Results First Received: March 25, 2010  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition: HIV Infections
Interventions: Drug: Optimized Background Therapy (OBT)
Drug: maraviroc (UK-427,857)

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Maraviroc QD Maraviroc 150 mg by mouth (PO) once daily (QD) in combination with optimized background therapy (OBT) (3 to 6 drugs based on treatment history and resistance testing). The 150 mg QD arm = placebo drug in the morning and active drug in the evening.
Maraviroc BID Maraviroc 150 mg PO twice a day (BID) in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The 150 mg BID arm = active drug in the morning and evening.
Placebo Placebo BID in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The placebo arm = placebo drug in the morning and evening.

Participant Flow for 3 periods

Period 1:   Assigned to Study Treatment
    Maraviroc QD   Maraviroc BID   Placebo
STARTED   63   63   64 
COMPLETED   63   61   62 
NOT COMPLETED   0   2   2 
Randomized, but not treated                0                2                2 

Period 2:   Received Study Treatment
    Maraviroc QD   Maraviroc BID   Placebo
STARTED   63   61 [1]   62 [2] 
Dual-tropic Subjects by Phenotype Assay   57 [3]   52   58 
COMPLETED   15   25   18 
NOT COMPLETED   48   36   44 
Death                2                1                2 
Adverse Event                1                2                5 
Lack of Efficacy                40                27                27 
Unspecified                2                2                6 
Subject defaulted                3                4                4 
[1] Due to 1 placebo subject switched to maraviroc BID, BID = 62 subjects in Adverse event tables.
[2] Due to 1 placebo subject switched to maraviroc BID, Placebo = 61 subjects in Adverse event tables.
[3] Dual-tropic: Virus capable of using both CCR5 and CXCR4 coreceptors for cell entry.

Period 3:   Continued on Open-Label Treatment
    Maraviroc QD   Maraviroc BID   Placebo
STARTED   15   25   0 [1] 
COMPLETED   7   10   0 
NOT COMPLETED   8   15   0 
Adverse Event                0                1                0 
Lack of Efficacy                1                2                0 
Other reason includes protocol violation                6                7                0 
Lost to Follow-up                1                1                0 
Withdrawal by Subject                0                4                0 
[1] Placebo group not offered open-label maraviroc due to study not reaching primary endpoint at Week 24



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Maraviroc QD Maraviroc 150 mg by mouth (PO) once daily (QD) in combination with optimized background therapy (OBT) (3 to 6 drugs based on treatment history and resistance testing). The 150 mg QD arm = placebo drug in the morning and active drug in the evening.
Maraviroc BID Maraviroc 150 mg PO twice a day (BID) in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The 150 mg BID arm = active drug in the morning and evening.
Placebo Placebo BID in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The placebo arm = placebo drug in the morning and evening.
Total Total of all reporting groups

Baseline Measures
   Maraviroc QD   Maraviroc BID   Placebo   Total 
Overall Participants Analyzed 
[Units: Participants]
 63   61   62   186 
Age, Customized 
[Units: Participants]
       
<18 years   2   2   0   4 
Between 18 and 24 years   1   1   1   3 
Between 25 and 34 years   2   3   2   7 
Between 35 and 44 years   30   31   31   92 
Between 45 and 54 years   25   21   20   66 
Between 55 and 64 years   3   3   7   13 
≥65 years   0   0   1   1 
Age 
[Units: Years]
Mean (Full Range)
 42.7 
 (16 to 59) 
 42.5 
 (16 to 62) 
 44.6 
 (23 to 65) 
 43.3 
 (16 to 65) 
Gender 
[Units: Participants]
       
Female   10   6   9   25 
Male   53   55   53   161 


  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   Change From Baseline in Human Immunodeficiency Virus (HIV-1) Viral Load (Ribonucleic Acid [RNA])   [ Time Frame: Baseline to Week 24 and Week 48 ]

Measure Type Primary
Measure Title Change From Baseline in Human Immunodeficiency Virus (HIV-1) Viral Load (Ribonucleic Acid [RNA])
Measure Description Change from baseline in log 10-transformed plasma viral load (HIV-1 RNA) levels (log 10 copies per milliliter [log10 copies/mL]). Baseline value calculated as average of pre-dose measurements collected at screening, randomization, and baseline visits.
Time Frame Baseline to Week 24 and Week 48  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full Analysis Set (FAS)-as treated: all randomized subjects classified as dual-tropic by phenotype assay; received at least 1 dose of study treatment. Missing values: discontinuations (DC) imputed as baseline value (change from baseline=0); missing data imputed as Last Observation Carried Forward (LOCF).

Reporting Groups
  Description
Maraviroc QD Maraviroc 150 mg by mouth (PO) once daily (QD) in combination with optimized background therapy (OBT) (3 to 6 drugs based on treatment history and resistance testing). The 150 mg QD arm = placebo drug in the morning and active drug in the evening.
Maraviroc BID Maraviroc 150 mg PO twice a day (BID) in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The 150 mg BID arm = active drug in the morning and evening.
Placebo Placebo BID in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The placebo arm = placebo drug in the morning and evening.

Measured Values
   Maraviroc QD   Maraviroc BID   Placebo 
Participants Analyzed 
[Units: Participants]
 57   52   58 
Change From Baseline in Human Immunodeficiency Virus (HIV-1) Viral Load (Ribonucleic Acid [RNA]) 
[Units: Log10 copies/mL]
Mean (Standard Error)
     
Week 24   -0.890  (0.1706)   -1.194  (0.2060)   -0.953  (0.1795) 
Week 48   -0.604  (0.1596)   -1.105  (0.2071)   0.839  (0.1851) 


Statistical Analysis 1 for Change From Baseline in Human Immunodeficiency Virus (HIV-1) Viral Load (Ribonucleic Acid [RNA])
Groups [1] Maraviroc QD vs. Placebo
Statistical Test Type [2] Non-Inferiority or Equivalence
Statistical Method [3] ANCOVA
Least squares mean [4] 0.055
97.5% Confidence Interval -0.528 to 0.638
Standard Error of the mean (0.2575)
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Maraviroc (MVC) QD versus placebo (PBO) treatment (TX) difference at Week 24. If upper bound of 97.5% confidence interval is <0, it is concluded that dose is superior to PBO. If upper bound is <0.25, it is concluded that MVC is non-inferior to PBO. Assumption: 79% of subjects are dual-tropic; total N=192 needed to be randomized to get N=150 dual-tropic. Standard deviation=0.8 with 2-sided p-value=0.025: 80% power for TX difference of 0.5 for change from baseline in log10-transformed viral load.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  For hypothesis of superiority, if upper bound of 97.5% confidence interval (CI) of TX difference was <0 log10 copies/mL, it was concluded that MVC regimen was superior to PBO meaning that MVC added to Optimized Background Therapy (OBT) provides an additional reduction in plasma HIV-1 RNA compared to OBT alone. If superiority could not be concluded, then a hypothesis of noninferiority was tested. If upper bound of CI is <0.25 log10 copies/mL, noninferiority of MVC regimen to placebo was claimed.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  TX difference adjusted for randomization strata. Bonferroni adjustment for multiple comparisons by use of 2-sided 97.5% CI to maintain alpha=0.05.
[4] Other relevant estimation information:
  Negative values for change from baseline=benefit of TX; negative values for MVC versus (vs) PBO=advantage of MVC.

Statistical Analysis 2 for Change From Baseline in Human Immunodeficiency Virus (HIV-1) Viral Load (Ribonucleic Acid [RNA])
Groups [1] Maraviroc BID vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] ANCOVA
Least squares mean [4] -0.232
97.5% Confidence Interval -0.829 to 0.364
Standard Error of the mean (0.2637)
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC BID vs PBO treatment difference at Week 24.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  TX difference adjusted for randomization strata. Bonferroni adjustment for multiple comparisons by use of 2-sided 97.5% CI to maintain alpha=0.05.
[4] Other relevant estimation information:
  Negative values for change from baseline=benefit of TX; negative values for MVC vs PBO=advantage of MVC.

Statistical Analysis 3 for Change From Baseline in Human Immunodeficiency Virus (HIV-1) Viral Load (Ribonucleic Acid [RNA])
Groups [1] Maraviroc QD vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] ANCOVA
Least squares mean [4] 0.229
97.5% Confidence Interval -0.351 to 0.810
Standard Error of the mean (0.2567)
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC QD vs PBO treatment difference at Week 48.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  TX difference adjusted for randomization strata. Bonferroni adjustment for multiple comparisons by use of 2-sided 97.5% CI to maintain alpha=0.05.
[4] Other relevant estimation information:
  Negative values for change from baseline=benefit of TX; negative values for MVC vs PBO=advantage of MVC.

Statistical Analysis 4 for Change From Baseline in Human Immunodeficiency Virus (HIV-1) Viral Load (Ribonucleic Acid [RNA])
Groups [1] Maraviroc BID vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] ANCOVA
Least squares mean [4] -0.261
97.5% Confidence Interval -0.856 to 0.333
Standard Error of the mean (0.2628)
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC BID vs PBO treatment difference at Week 48.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  TX difference adjusted for randomization strata. Bonferroni adjustment for multiple comparisons by use of 2-sided 97.5% CI to maintain alpha=0.05.
[4] Other relevant estimation information:
  Negative values for change from baseline=benefit of TX; negative values for MVC vs PBO=advantage of MVC.



2.  Secondary:   Number of Subjects With HIV-1 RNA Levels < 400 Copies/mL   [ Time Frame: Week 24, Week 48 ]

Measure Type Secondary
Measure Title Number of Subjects With HIV-1 RNA Levels < 400 Copies/mL
Measure Description No text entered.
Time Frame Week 24, Week 48  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS - as treated dual-tropic subjects. Missing values counted as failures/non-responders (counted as not achieving the stated criterion).

Reporting Groups
  Description
Maraviroc QD Maraviroc 150 mg by mouth (PO) once daily (QD) in combination with optimized background therapy (OBT) (3 to 6 drugs based on treatment history and resistance testing). The 150 mg QD arm = placebo drug in the morning and active drug in the evening.
Maraviroc BID Maraviroc 150 mg PO twice a day (BID) in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The 150 mg BID arm = active drug in the morning and evening.
Placebo Placebo BID in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The placebo arm = placebo drug in the morning and evening.

Measured Values
   Maraviroc QD   Maraviroc BID   Placebo 
Participants Analyzed 
[Units: Participants]
 57   52   58 
Number of Subjects With HIV-1 RNA Levels < 400 Copies/mL 
[Units: Participants]
     
Week 24   14   16   14 
Week 48   13   16   13 


Statistical Analysis 1 for Number of Subjects With HIV-1 RNA Levels < 400 Copies/mL
Groups [1] Maraviroc QD vs. Placebo
Statistical Test Type [2] Superiority or Other
difference in proportions [3] 0.03
95% Confidence Interval -0.12 to 0.18
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC QD vs PBO treatment difference in proportions at Week 24.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  The TX difference is weighted (by inverse of the variance) difference in proportions adjusted for randomization strata. Positive values for TX difference favor MVC. CI estimated using the normal approximation to the binomial distribution.

Statistical Analysis 2 for Number of Subjects With HIV-1 RNA Levels < 400 Copies/mL
Groups [1] Maraviroc BID vs. Placebo
Statistical Test Type [2] Superiority or Other
difference in proportions [3] 0.07
95% Confidence Interval -0.08 to 0.23
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC BID vs PBO treatment difference in proportions at Week 24.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  The TX difference is weighted (by inverse of the variance) difference in proportions adjusted for randomization strata. Positive values for TX difference favor MVC. CI estimated using the normal approximation to the binomial distribution.

Statistical Analysis 3 for Number of Subjects With HIV-1 RNA Levels < 400 Copies/mL
Groups [1] Maraviroc QD vs. Placebo
Statistical Test Type [2] Superiority or Other
difference in proportions [3] 0.02
95% Confidence Interval -0.12 to 0.17
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC QD vs PBO treatment difference in proportions at Week 48.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  The TX difference is weighted (by inverse of the variance) difference in proportions adjusted for randomization strata. Positive values for TX difference favor MVC. CI estimated using the normal approximation to the binomial distribution.

Statistical Analysis 4 for Number of Subjects With HIV-1 RNA Levels < 400 Copies/mL
Groups [1] Maraviroc BID vs. Placebo
Statistical Test Type [2] Superiority or Other
difference in proportions [3] 0.09
95% Confidence Interval -0.07 to 0.25
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC BID vs PBO treatment difference in proportions at Week 48.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  The TX difference is weighted (by inverse of the variance) difference in proportions adjusted for randomization strata. Positive values for TX difference favor MVC. CI estimated using the normal approximation to the binomial distribution.



3.  Secondary:   Number of Subjects With HIV-1 RNA Levels < 400 Copies/mL or at Least 0.5 Log 10-transformed Decrease From Baseline in HIV-1 RNA Levels   [ Time Frame: Baseline, Week 24, Week 48 ]

Measure Type Secondary
Measure Title Number of Subjects With HIV-1 RNA Levels < 400 Copies/mL or at Least 0.5 Log 10-transformed Decrease From Baseline in HIV-1 RNA Levels
Measure Description Number of subjects with HIV-1 RNA levels < 400 copies/mL or at least 0.5 log 10-transformed decrease from baseline in HIV-1 RNA levels. Baseline value calculated as average of pre-dose measurements collected at screening, randomization, and baseline visits.
Time Frame Baseline, Week 24, Week 48  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS-as treated dual-tropic subjects. Missing values counted as failures/non-responders (counted as not achieving the stated criterion).

Reporting Groups
  Description
Maraviroc QD Maraviroc 150 mg by mouth (PO) once daily (QD) in combination with optimized background therapy (OBT) (3 to 6 drugs based on treatment history and resistance testing). The 150 mg QD arm = placebo drug in the morning and active drug in the evening.
Maraviroc BID Maraviroc 150 mg PO twice a day (BID) in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The 150 mg BID arm = active drug in the morning and evening.
Placebo Placebo BID in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The placebo arm = placebo drug in the morning and evening.

Measured Values
   Maraviroc QD   Maraviroc BID   Placebo 
Participants Analyzed 
[Units: Participants]
 57   52   58 
Number of Subjects With HIV-1 RNA Levels < 400 Copies/mL or at Least 0.5 Log 10-transformed Decrease From Baseline in HIV-1 RNA Levels 
[Units: Participants]
     
Week 24   24   25   23 
Week 48   14   22   18 


Statistical Analysis 1 for Number of Subjects With HIV-1 RNA Levels < 400 Copies/mL or at Least 0.5 Log 10-transformed Decrease From Baseline in HIV-1 RNA Levels
Groups [1] Maraviroc QD vs. Placebo
Statistical Test Type [2] Superiority or Other
difference in proportions [3] 0.03
95% Confidence Interval -0.15 to 0.20
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC QD vs PBO treatment difference in proportions at Week 24.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  The TX difference is weighted (by inverse of the variance) difference in proportions adjusted for randomization strata. Positive values for TX difference favor MVC. CI estimated using the normal approximation to the binomial distribution.

Statistical Analysis 2 for Number of Subjects With HIV-1 RNA Levels < 400 Copies/mL or at Least 0.5 Log 10-transformed Decrease From Baseline in HIV-1 RNA Levels
Groups [1] Maraviroc BID vs. Placebo
Statistical Test Type [2] Superiority or Other
difference in proportions [3] 0.08
95% Confidence Interval -0.10 to 0.26
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC BID vs PBO treatment difference in proportions at Week 24.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  The TX difference is weighted (by inverse of the variance) difference in proportions adjusted for randomization strata. Positive values for TX difference favor MVC. CI estimated using the normal approximation to the binomial distribution.

Statistical Analysis 3 for Number of Subjects With HIV-1 RNA Levels < 400 Copies/mL or at Least 0.5 Log 10-transformed Decrease From Baseline in HIV-1 RNA Levels
Groups [1] Maraviroc QD vs. Placebo
Statistical Test Type [2] Superiority or Other
difference in proportions [3] -0.06
95% Confidence Interval -0.22 to 0.10
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC QD vs PBO treatment difference in proportions at Week 48.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  The TX difference is weighted (by inverse of the variance) difference in proportions adjusted for randomization strata. Positive values for TX difference favor MVC. CI estimated using the normal approximation to the binomial distribution.

Statistical Analysis 4 for Number of Subjects With HIV-1 RNA Levels < 400 Copies/mL or at Least 0.5 Log 10-transformed Decrease From Baseline in HIV-1 RNA Levels
Groups [1] Maraviroc BID vs. Placebo
Statistical Test Type [2] Superiority or Other
difference in proportions [3] 0.11
95% Confidence Interval -0.07 to 0.28
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC BID vs PBO treatment difference in proportions at Week 48.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  The TX difference is weighted (by inverse of the variance) difference in proportions adjusted for randomization strata. Positive values for TX difference favor MVC. CI estimated using the normal approximation to the binomial distribution.



4.  Secondary:   Number of Subjects With HIV-1 RNA Levels < 400 Copies/mL or at Least 1.0 Log 10-transformed Decrease From Baseline in HIV-1 RNA Levels   [ Time Frame: Baseline, Week 24, Week 48 ]

Measure Type Secondary
Measure Title Number of Subjects With HIV-1 RNA Levels < 400 Copies/mL or at Least 1.0 Log 10-transformed Decrease From Baseline in HIV-1 RNA Levels
Measure Description Number of subjects with HIV-1 RNA levels < 400 copies/mL or at least 1.0 log 10-transformed decrease from baseline in HIV-1 RNA levels. Baseline value calculated as average of pre-dose measurements collected at screening, randomization, and baseline visits.
Time Frame Baseline, Week 24, Week 48  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS-as treated dual-tropic subjects. Missing values counted as failures/non-responders (counted as not achieving the stated criterion).

Reporting Groups
  Description
Maraviroc QD Maraviroc 150 mg by mouth (PO) once daily (QD) in combination with optimized background therapy (OBT) (3 to 6 drugs based on treatment history and resistance testing). The 150 mg QD arm = placebo drug in the morning and active drug in the evening.
Maraviroc BID Maraviroc 150 mg PO twice a day (BID) in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The 150 mg BID arm = active drug in the morning and evening.
Placebo Placebo BID in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The placebo arm = placebo drug in the morning and evening.

Measured Values
   Maraviroc QD   Maraviroc BID   Placebo 
Participants Analyzed 
[Units: Participants]
 57   52   58 
Number of Subjects With HIV-1 RNA Levels < 400 Copies/mL or at Least 1.0 Log 10-transformed Decrease From Baseline in HIV-1 RNA Levels 
[Units: Participants]
     
Week 24   18   23   21 
Week 48   13   20   15 


Statistical Analysis 1 for Number of Subjects With HIV-1 RNA Levels < 400 Copies/mL or at Least 1.0 Log 10-transformed Decrease From Baseline in HIV-1 RNA Levels
Groups [1] Maraviroc QD vs. Placebo
Statistical Test Type [2] Superiority or Other
difference in proportions [3] -0.05
95% Confidence Interval -0.21 to 0.12
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC QD vs PBO treatment difference in proportions at Week 24.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  The TX difference is weighted (by inverse of the variance) difference in proportions adjusted for randomization strata. Positive values for TX difference favor MVC. CI estimated using the normal approximation to the binomial distribution.

Statistical Analysis 2 for Number of Subjects With HIV-1 RNA Levels < 400 Copies/mL or at Least 1.0 Log 10-transformed Decrease From Baseline in HIV-1 RNA Levels
Groups [1] Maraviroc BID vs. Placebo
Statistical Test Type [2] Superiority or Other
difference in proportions [3] 0.08
95% Confidence Interval -0.10 to 0.26
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC BID vs PBO treatment difference in proportions at Week 24.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  The TX difference is weighted (by inverse of the variance) difference in proportions adjusted for randomization strata. Positive values for TX difference favor MVC. CI estimated using the normal approximation to the binomial distribution.

Statistical Analysis 3 for Number of Subjects With HIV-1 RNA Levels < 400 Copies/mL or at Least 1.0 Log 10-transformed Decrease From Baseline in HIV-1 RNA Levels
Groups [1] Maraviroc QD vs. Placebo
Statistical Test Type [2] Superiority or Other
difference in proportions [3] -0.02
95% Confidence Interval -0.18 to 0.13
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC QD vs PBO treatment difference in proportions at Week 48.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  The TX difference is weighted (by inverse of the variance) difference in proportions adjusted for randomization strata. Positive values for TX difference favor MVC. CI estimated using the normal approximation to the binomial distribution.

Statistical Analysis 4 for Number of Subjects With HIV-1 RNA Levels < 400 Copies/mL or at Least 1.0 Log 10-transformed Decrease From Baseline in HIV-1 RNA Levels
Groups [1] Maraviroc BID vs. Placebo
Statistical Test Type [2] Superiority or Other
difference in proportions [3] 0.12
95% Confidence Interval -0.04 to 0.29
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC BID vs PBO treatment difference in proportions at Week 48.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  The TX difference is weighted (by inverse of the variance) difference in proportions adjusted for randomization strata. Positive values for TX difference favor MVC. CI estimated using the normal approximation to the binomial distribution.



5.  Secondary:   Number of Subjects With HIV-1 RNA Levels < 50 Copies/mL   [ Time Frame: Baseline, Week 24, Week 48 ]

Measure Type Secondary
Measure Title Number of Subjects With HIV-1 RNA Levels < 50 Copies/mL
Measure Description No text entered.
Time Frame Baseline, Week 24, Week 48  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS - as treated dual-tropic subjects. Missing values counted as failures/non-responders (counted as not achieving the stated criterion).

Reporting Groups
  Description
Maraviroc QD Maraviroc 150 mg by mouth (PO) once daily (QD) in combination with optimized background therapy (OBT) (3 to 6 drugs based on treatment history and resistance testing). The 150 mg QD arm = placebo drug in the morning and active drug in the evening.
Maraviroc BID Maraviroc 150 mg PO twice a day (BID) in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The 150 mg BID arm = active drug in the morning and evening.
Placebo Placebo BID in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The placebo arm = placebo drug in the morning and evening.

Measured Values
   Maraviroc QD   Maraviroc BID   Placebo 
Participants Analyzed 
[Units: Participants]
 57   52   58 
Number of Subjects With HIV-1 RNA Levels < 50 Copies/mL 
[Units: Participants]
     
Week 24   12   14   9 
Week 48   10   14   13 


Statistical Analysis 1 for Number of Subjects With HIV-1 RNA Levels < 50 Copies/mL
Groups [1] Maraviroc QD vs. Placebo
Statistical Test Type [2] Superiority or Other
difference in proportions [3] 0.07
95% Confidence Interval -0.07 to 0.20
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC QD vs PBO treatment difference in proportions at Week 24.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  The TX difference is weighted (by inverse of the variance) difference in proportions adjusted for randomization strata. Positive values for TX difference favor MVC. CI estimated using the normal approximation to the binomial distribution.

Statistical Analysis 2 for Number of Subjects With HIV-1 RNA Levels < 50 Copies/mL
Groups [1] Maraviroc BID vs. Placebo
Statistical Test Type [2] Superiority or Other
difference in proportions [3] 0.11
95% Confidence Interval -0.03 to 0.26
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC BID vs PBO difference in proportions at Week 24.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  The TX difference is weighted (by inverse of the variance) difference in proportions adjusted for randomization strata. Positive values for TX difference favor MVC. CI estimated using the normal approximation to the binomial distribution.

Statistical Analysis 3 for Number of Subjects With HIV-1 RNA Levels < 50 Copies/mL
Groups [1] Maraviroc QD vs. Placebo
Statistical Test Type [2] Superiority or Other
difference in proportions [3] -0.04
95% Confidence Interval -0.18 to 0.10
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC QD vs PBO treatment difference in proportions at Week 48.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  The TX difference is weighted (by inverse of the variance) difference in proportions adjusted for randomization strata. Positive values for TX difference favor MVC. CI estimated using the normal approximation to the binomial distribution.

Statistical Analysis 4 for Number of Subjects With HIV-1 RNA Levels < 50 Copies/mL
Groups [1] Maraviroc BID vs. Placebo
Statistical Test Type [2] Superiority or Other
difference in proportions [3] 0.06
95% Confidence Interval -0.10 to 0.21
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC BID vs PBO treatment difference in proportions at Week 48.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  The TX difference is weighted (by inverse of the variance) difference in proportions adjusted for randomization strata. Positive values for TX difference favor MVC. CI estimated using the normal approximation to the binomial distribution.



6.  Secondary:   Change From Baseline in CD4 Cell Count   [ Time Frame: Baseline to Week 24 and Week 48 ]

Measure Type Secondary
Measure Title Change From Baseline in CD4 Cell Count
Measure Description Change from baseline in CD4 cell count (measured as cells per microliter [cells/µL]). Baseline value calculated as the average of pre-dose measurements collected at screening, randomization, and baseline visits.
Time Frame Baseline to Week 24 and Week 48  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS - as treated dual-tropic subjects. Placebo N: 4 subjects did not have on-treatment information. Missing data imputed using LOCF.

Reporting Groups
  Description
Maraviroc QD Maraviroc 150 mg by mouth (PO) once daily (QD) in combination with optimized background therapy (OBT) (3 to 6 drugs based on treatment history and resistance testing). The 150 mg QD arm = placebo drug in the morning and active drug in the evening.
Maraviroc BID Maraviroc 150 mg PO twice a day (BID) in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The 150 mg BID arm = active drug in the morning and evening.
Placebo Placebo BID in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The placebo arm = placebo drug in the morning and evening.

Measured Values
   Maraviroc QD   Maraviroc BID   Placebo 
Participants Analyzed 
[Units: Participants]
 57   52   54 
Change From Baseline in CD4 Cell Count 
[Units: cells/µL]
Mean (Standard Error)
     
Week 24   59.237  (8.9661)   62.651  (10.0234)   36.367  (8.4477) 
Week 48   65.86  (10.822)   78.87  (11.566)   51.29  (12.523) 


Statistical Analysis 1 for Change From Baseline in CD4 Cell Count
Groups [1] Maraviroc QD vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] ANCOVA
Least squares mean [4] 23.927
95% Confidence Interval -1.359 to 49.213
Standard Error of the mean (12.8025)
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC QD vs PBO treatment difference at Week 24.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  TX difference adjusted for randomization strata.
[4] Other relevant estimation information:
  Negative values for change from baseline=benefit of TX; negative values for MVC vs PBO=advantage of MVC.

Statistical Analysis 2 for Change From Baseline in CD4 Cell Count
Groups [1] Maraviroc BID vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] ANCOVA
Least squares mean [4] 26.679
95% Confidence Interval 0.869 to 52.490
Standard Error of the mean (13.0678)
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC BID vs PBO treatment difference at Week 24.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  TX difference adjusted for randomization strata.
[4] Other relevant estimation information:
  Negative values for change from baseline=benefit of TX; negative values for MVC vs PBO=advantage of MVC.

Statistical Analysis 3 for Change From Baseline in CD4 Cell Count
Groups [1] Maraviroc QD vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] ANCOVA
Least squares mean [4] 14.61
95% Confidence Interval -17.80 to 47.03
Standard Error of the mean (16.412)
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC QD vs PBO treatment difference at Week 48.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  TX difference adjusted for randomization strata.
[4] Other relevant estimation information:
  Negative values for change from baseline=benefit of TX; negative values for MVC vs PBO=advantage of MVC.

Statistical Analysis 4 for Change From Baseline in CD4 Cell Count
Groups [1] Maraviroc BID vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] ANCOVA
Least squares mean [4] 27.71
95% Confidence Interval -5.38 to 60.80
Standard Error of the mean (16.754)
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC BID vs PBO treatment difference at Week 48.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  TX difference adjusted for randomization strata.
[4] Other relevant estimation information:
  Negative values for change from baseline=benefit of TX; negative values for MVC vs PBO=advantage of MVC.



7.  Secondary:   Change From Baseline in CD8 Cell Count   [ Time Frame: Baseline to Week 24 and Week 48 ]

Measure Type Secondary
Measure Title Change From Baseline in CD8 Cell Count
Measure Description Change from baseline in CD8 cell count (measured as cells/µL). Baseline value calculated as the average of pre-dose measurements collected at screening, randomization, and baseline visits.
Time Frame Baseline to Week 24 and Week 48  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS - as treated dual-tropic subjects. Placebo N: 4 subjects did not have on-treatment information. Missing data imputed using LOCF.

Reporting Groups
  Description
Maraviroc QD Maraviroc 150 mg by mouth (PO) once daily (QD) in combination with optimized background therapy (OBT) (3 to 6 drugs based on treatment history and resistance testing). The 150 mg QD arm = placebo drug in the morning and active drug in the evening.
Maraviroc BID Maraviroc 150 mg PO twice a day (BID) in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The 150 mg BID arm = active drug in the morning and evening.
Placebo Placebo BID in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The placebo arm = placebo drug in the morning and evening.

Measured Values
   Maraviroc QD   Maraviroc BID   Placebo 
Participants Analyzed 
[Units: Participants]
 57   52   54 
Change From Baseline in CD8 Cell Count 
[Units: cells/µL]
Mean (Standard Error)
     
Week 24   391.061  (57.0135)   322.683  (68.3315)   154.293  (46.8100) 
Week 48   351.23  (54.653)   342.87  (72.222)   192.30  (62.578) 


Statistical Analysis 1 for Change From Baseline in CD8 Cell Count
Groups [1] Maraviroc QD vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] ANCOVA
Least squares mean [4] 234.499
95% Confidence Interval 74.913 to 394.084
Standard Error of the mean (80.7990)
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC QD vs PBO treatment difference at Week 24.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  TX difference adjusted for randomization strata.
[4] Other relevant estimation information:
  Negative values for change from baseline=benefit of TX; negative values for MVC vs PBO=advantage of MVC.

Statistical Analysis 2 for Change From Baseline in CD8 Cell Count
Groups [1] Maraviroc BID vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] ANCOVA
Least squares mean [4] 188.817
95% Confidence Interval 23.999 to 353.635
Standard Error of the mean (83.4484)
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC BID vs PBO treatment difference at Week 24.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  TX difference adjusted for randomization strata.
[4] Other relevant estimation information:
  Negative values for change from baseline=benefit of TX; negative values for MVC vs PBO=advantage of MVC.

Statistical Analysis 3 for Change From Baseline in CD8 Cell Count
Groups [1] Maraviroc QD vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] ANCOVA
Least squares mean [4] 155.94
95% Confidence Interval -16.49 to 328.37
Standard Error of the mean (87.304)
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC QD vs PBO treatment difference at Week 48.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  TX difference adjusted for randomization strata.
[4] Other relevant estimation information:
  Negative values for change from baseline=benefit of TX; negative values for MVC vs PBO=advantage of MVC.

Statistical Analysis 4 for Change From Baseline in CD8 Cell Count
Groups [1] Maraviroc BID vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] ANCOVA
Least squares mean [4] 182.91
95% Confidence Interval 4.81 to 361.02
Standard Error of the mean (90.174)
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC BID vs PBO treatment difference at Week 48.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  TX difference adjusted for randomization strata.
[4] Other relevant estimation information:
  Negative values for change from baseline=benefit of TX; negative values for MVC vs PBO=advantage of MVC.



8.  Secondary:   Time (50% Quartile Point Estimate) to Virologic Failure   [ Time Frame: Day 1 through Week 24 and through Week 48 ]

Measure Type Secondary
Measure Title Time (50% Quartile Point Estimate) to Virologic Failure
Measure Description Time to virologic failure based on observed HIV-1 RNA levels and failure events (death; permanent discontinuation of test drug [perm DC]; lost to follow-up [LTFU]; new anti-retroviral drug added (except background drug change to drug of same class); or on open label for early non-response or rebound). Failure: at Time 0 if level not <400 copies/mL (2 consecutive visits) before event(s) or last available visit; at time of earliest event if level <400 copies/mL (on 2 consecutive visits); failure if level ≥400 copies/mL (2 consecutive visits) or 1 visit ≥400 copies/mL followed by perm DC or LTFU.
Time Frame Day 1 through Week 24 and through Week 48  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS - as treated dual-tropic subjects; (n)=number of subjects with virologic failure at observation for maraviroc QD, maraviroc BID, and placebo, respectively; Week 48 result values (0.00)=virologic failure at Day 0.

Reporting Groups
  Description
Maraviroc QD Maraviroc 150 mg by mouth (PO) once daily (QD) in combination with optimized background therapy (OBT) (3 to 6 drugs based on treatment history and resistance testing). The 150 mg QD arm = placebo drug in the morning and active drug in the evening.
Maraviroc BID Maraviroc 150 mg PO twice a day (BID) in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The 150 mg BID arm = active drug in the morning and evening.
Placebo Placebo BID in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The placebo arm = placebo drug in the morning and evening.

Measured Values
   Maraviroc QD   Maraviroc BID   Placebo 
Participants Analyzed 
[Units: Participants]
 57   52   58 
Time (50% Quartile Point Estimate) to Virologic Failure 
[Units: Days]
Median (95% Confidence Interval)
     
Week 24 (n=35, 23, 29)   88.00 [1] 
 (59.00 to N/A) 
 189.00 
 (113.00 to 189.00) 
 100.00 [1] 
 (60.00 to N/A) 
Week 48 (n=45, 37, 44)   0.00 [2]   0.00 
 (0.00 to 142.00) 
 0.00 
 (0.00 to 29.00) 
[1] Parameter was not calculable.
[2] Parameters were not calculable.


Statistical Analysis 1 for Time (50% Quartile Point Estimate) to Virologic Failure
Groups [1] Maraviroc QD vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Log Rank
P Value [4] 0.7524
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC QD vs PBO at Week 24. Kaplan-Meier survival estimates. TX difference evaluated by log-rank test.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.

Statistical Analysis 2 for Time (50% Quartile Point Estimate) to Virologic Failure
Groups [1] Maraviroc BID vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Log Rank
P Value [4] 0.2540
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC BID vs PBO at Week 24. Kaplan-Meier survival estimates. TX difference evaluated by log-rank test.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.

Statistical Analysis 3 for Time (50% Quartile Point Estimate) to Virologic Failure
Groups [1] Maraviroc QD vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Log Rank
P Value [4] 0.8243
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC QD vs PBO at Week 48. Kaplan-Meier survival estimates. TX difference evaluated by log-rank test.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.

Statistical Analysis 4 for Time (50% Quartile Point Estimate) to Virologic Failure
Groups [1] Maraviroc BID vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Log Rank
P Value [4] 0.6657
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC BID vs PBO at Week 48. Kaplan-Meier survival estimates. TX difference evaluated by log-rank test.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.



9.  Secondary:   Change From Baseline in Time Averaged Difference (TAD) in log10 HIV-1 RNA   [ Time Frame: Baseline to Week 24 and Week 48 ]

Measure Type Secondary
Measure Title Change From Baseline in Time Averaged Difference (TAD) in log10 HIV-1 RNA
Measure Description Change from baseline of TAD in log10 HIV-1 RNA viral load calculated as [AUC of HIV-1 RNA viral load (log10 copies/mL) / time period] - Baseline HIV-1 RNA viral load (log10 copies/mL). Baseline value calculated as the average of pre-dose measurements collected at screening, randomization, and baseline visits.
Time Frame Baseline to Week 24 and Week 48  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS - as treated dual-tropic subjects. Discontinuations prior to time point of analysis imputed as 0.

Reporting Groups
  Description
Maraviroc QD Maraviroc 150 mg by mouth (PO) once daily (QD) in combination with optimized background therapy (OBT) (3 to 6 drugs based on treatment history and resistance testing). The 150 mg QD arm = placebo drug in the morning and active drug in the evening.
Maraviroc BID Maraviroc 150 mg PO twice a day (BID) in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The 150 mg BID arm = active drug in the morning and evening.
Placebo Placebo BID in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The placebo arm = placebo drug in the morning and evening.

Measured Values
   Maraviroc QD   Maraviroc BID   Placebo 
Participants Analyzed 
[Units: Participants]
 57   52   58 
Change From Baseline in Time Averaged Difference (TAD) in log10 HIV-1 RNA 
[Units: Log10 copies/mL]
Mean (Standard Error)
     
Week 24   -0.850  (0.1510)   -1.151  (0.1895)   -0.926  (0.1679) 
Week 48   -0.561  (0.1475)   -1.066  (0.1962)   -0.776  (0.1700) 


Statistical Analysis 1 for Change From Baseline in Time Averaged Difference (TAD) in log10 HIV-1 RNA
Groups [1] Maraviroc QD vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] ANCOVA
Least squares mean [4] 0.069
95% Confidence Interval -0.396 to 0.535
Standard Error of the mean (0.2356)
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC QD vs PBO treatment difference at Week 24.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  TX difference adjusted for randomization strata.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Change From Baseline in Time Averaged Difference (TAD) in log10 HIV-1 RNA
Groups [1] Maraviroc BID vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] ANCOVA
Least squares mean [4] -0.218
95% Confidence Interval -0.694 to 0.258
Standard Error of the mean (0.2413)
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC BID vs PBO treatment difference at Week 24.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  TX difference adjusted for randomization strata.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 3 for Change From Baseline in Time Averaged Difference (TAD) in log10 HIV-1 RNA
Groups [1] Maraviroc QD vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] ANCOVA
Least squares mean [4] 0.209
95% Confidence Interval -0.262 to 0.681
Standard Error of the mean (0.2388)
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC QD vs PBO treatment difference at Week 48.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  TX difference adjusted for randomization strata.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 4 for Change From Baseline in Time Averaged Difference (TAD) in log10 HIV-1 RNA
Groups [1] Maraviroc BID vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] ANCOVA
Least squares mean [4] -0.284
95% Confidence Interval -0.767 to 0.199
Standard Error of the mean (0.2445)
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC BID vs PBO treatment difference at Week 48.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  TX difference adjusted for randomization strata.
[4] Other relevant estimation information:
  No text entered.



10.  Secondary:   Number of Subjects Per Genotype and Phenotype at Baseline and at Time of Failure   [ Time Frame: Baseline through Week 48 ]

Measure Type Secondary
Measure Title Number of Subjects Per Genotype and Phenotype at Baseline and at Time of Failure
Measure Description Number of subjects per genotype and phenotype (tests for presence of non CCR5-tropic HIV-1 and for resistance to reverse transcriptase, protease, and fusion inhibitors) at baseline and at time of failure through Week 48 visit. Sensitivity to drug categorized as 0-1, 2-4, >4; scores defined as 0=resistance, 1=sensitive or susceptible with higher number indicating greater sensitivity or susceptibility.
Time Frame Baseline through Week 48  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS-as treated dual-tropic subjects. Genotype and phenotype at screening and at time of failure were not summarized as planned.

Reporting Groups
  Description
Maraviroc QD Maraviroc 150 mg by mouth (PO) once daily (QD) in combination with optimized background therapy (OBT) (3 to 6 drugs based on treatment history and resistance testing). The 150 mg QD arm = placebo drug in the morning and active drug in the evening.
Maraviroc BID Maraviroc 150 mg PO twice a day (BID) in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The 150 mg BID arm = active drug in the morning and evening.
Placebo Placebo BID in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The placebo arm = placebo drug in the morning and evening.

Measured Values
   Maraviroc QD   Maraviroc BID   Placebo 
Participants Analyzed 
[Units: Participants]
 0   0   0 
Number of Subjects Per Genotype and Phenotype at Baseline and at Time of Failure 
[Units: Participants]
        

No statistical analysis provided for Number of Subjects Per Genotype and Phenotype at Baseline and at Time of Failure



11.  Secondary:   Number of Subjects Per Tropism Status at Screening and at the Time of Treatment Failure (Analysis at Week 24)   [ Time Frame: Screening through Week 24 ]

Measure Type Secondary
Measure Title Number of Subjects Per Tropism Status at Screening and at the Time of Treatment Failure (Analysis at Week 24)
Measure Description Number of subjects per Tropism status (CCR5 [R5], CXCR4 [X4], Dual Mixed [DM], or Non-reportable/Non-phenotypable [NR/NP]) at Screening (Scr) and at time of treatment failure (Tx fail). Treatment failure defined as insufficient clinical response. HIV-1 RNA viral load <500 copies/ml categorized as below lower limit of quantification (BLQ). Tropism may have been assessed at either the Screening or Baseline visit. The assessment for time of treatment failure is defined as the last on-treatment assessment.
Time Frame Screening through Week 24  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS-as treated; N=subjects with TX failure due to insufficient clinical response and who had a tropism assessment at Screening. Subjects with DC prior to timepoint not included; LOCF if no result (viral load too low for analysis).

Reporting Groups
  Description
Maraviroc QD Maraviroc 150 mg by mouth (PO) once daily (QD) in combination with optimized background therapy (OBT) (3 to 6 drugs based on treatment history and resistance testing). The 150 mg QD arm = placebo drug in the morning and active drug in the evening.
Maraviroc BID Maraviroc 150 mg PO twice a day (BID) in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The 150 mg BID arm = active drug in the morning and evening.
Placebo Placebo BID in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The placebo arm = placebo drug in the morning and evening.

Measured Values
   Maraviroc QD   Maraviroc BID   Placebo 
Participants Analyzed 
[Units: Participants]
 35   24   24 
Number of Subjects Per Tropism Status at Screening and at the Time of Treatment Failure (Analysis at Week 24) 
[Units: Participants]
     
Scr: X4, Tx fail: X4   1   1   1 
Scr: X4, Tx fail: DM   1   1   0 
Scr: DM, Tx fail: R5   1   0   4 
Scr: DM, Tx fail: X4   12   12   2 
Scr: DM, Tx fail: DM   19   9   16 
Scr DM, Tx fail: NR/NP   0   0   1 
Scr DM, Tx fail: BLQ   1   0   0 
Scr NR/NP, Tx fail: NR/NP   0   1   0 

No statistical analysis provided for Number of Subjects Per Tropism Status at Screening and at the Time of Treatment Failure (Analysis at Week 24)



12.  Secondary:   Number of Subjects Per Tropism Status at Screening and Time of Treatment Failure (Analysis at Week 48)   [ Time Frame: Screening through Week 48 ]

Measure Type Secondary
Measure Title Number of Subjects Per Tropism Status at Screening and Time of Treatment Failure (Analysis at Week 48)
Measure Description Number of subjects per Tropism status (CCR5 [R5], CXCR4 [X4], Dual Mixed [DM], or Non-reportable/Non-phenotypable [NR/NP]) at Screening (Scr) and at time of treatment failure (Tx fail). Treatment failure defined as insufficient clinical response. HIV-1 RNA viral load <500 copies/ml categorized as below lower limit of quantification (BLQ). Tropism may have been assessed at either the Screening or Baseline visit. The assessment for time of treatment failure is defined as the last on-treatment assessment.
Time Frame Screening through Week 48  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS-as treated; N=subjects with TX failure due to insufficient clinical response and who had a tropism assessment at Screening. Subjects with DC prior to timepoint not included; LOCF if no result (viral load too low for analysis).

Reporting Groups
  Description
Maraviroc QD Maraviroc 150 mg by mouth (PO) once daily (QD) in combination with optimized background therapy (OBT) (3 to 6 drugs based on treatment history and resistance testing). The 150 mg QD arm = placebo drug in the morning and active drug in the evening.
Maraviroc BID Maraviroc 150 mg PO twice a day (BID) in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The 150 mg BID arm = active drug in the morning and evening.
Placebo Placebo BID in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The placebo arm = placebo drug in the morning and evening.

Measured Values
   Maraviroc QD   Maraviroc BID   Placebo 
Participants Analyzed 
[Units: Participants]
 40   27   27 
Number of Subjects Per Tropism Status at Screening and Time of Treatment Failure (Analysis at Week 48) 
[Units: Participants]
     
Scr: X4, Tx fail: X4   1   1   1 
Scr: X4, Tx fail: DM   1   1   0 
Scr: DM, Tx fail: R5   1   1   5 
Scr: DM, Tx fail: X4   12   12   2 
Scr: DM, Tx fail: DM   24   10   18 
Scr: DM, Tx fail: NR/NP   0   1   1 
Scr: DM, Tx fail: BLQ   1   0   0 
Scr: NR/NP, Tx fail: NR/NP   0   1   0 

No statistical analysis provided for Number of Subjects Per Tropism Status at Screening and Time of Treatment Failure (Analysis at Week 48)



13.  Secondary:   Number of Subjects With Treatment Failure at Week 24 by Overall Susceptibility Score (OSS) at Screening   [ Time Frame: Screening, Week 24 ]

Measure Type Secondary
Measure Title Number of Subjects With Treatment Failure at Week 24 by Overall Susceptibility Score (OSS) at Screening
Measure Description Number of subjects for association between screening resistance and virologic response as determined by treatment failure and OSS at screening. OSS categorized as 0-1, 2-4, >4 (maximum value of 6) and calculated as the sum of the net assessment of in vitro phenotypic and genotypic susceptibility using a binary scoring system (0= reduced susceptibility, 1=susceptible) for each antiretroviral agent in OBT. Higher scores indicate greater susceptibility.
Time Frame Screening, Week 24  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS - as treated dual-tropic subjects. Missing values imputed as LOCF.

Reporting Groups
  Description
Maraviroc QD Maraviroc 150 mg by mouth (PO) once daily (QD) in combination with optimized background therapy (OBT) (3 to 6 drugs based on treatment history and resistance testing). The 150 mg QD arm = placebo drug in the morning and active drug in the evening.
Maraviroc BID Maraviroc 150 mg PO twice a day (BID) in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The 150 mg BID arm = active drug in the morning and evening.
Placebo Placebo BID in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The placebo arm = placebo drug in the morning and evening.

Measured Values
   Maraviroc QD   Maraviroc BID   Placebo 
Participants Analyzed 
[Units: Participants]
 57   52   58 
Number of Subjects With Treatment Failure at Week 24 by Overall Susceptibility Score (OSS) at Screening 
[Units: Participants]
     
Scr score: 0-1   21   12   17 
Scr score: 2-4   35   35   40 
Scr score: missing   1   1   1 

No statistical analysis provided for Number of Subjects With Treatment Failure at Week 24 by Overall Susceptibility Score (OSS) at Screening



14.  Secondary:   Number of Subjects With Treatment Failure at Week 48 by Overall Susceptibility Score (OSS) at Screening   [ Time Frame: Screening, Week48 ]

Measure Type Secondary
Measure Title Number of Subjects With Treatment Failure at Week 48 by Overall Susceptibility Score (OSS) at Screening
Measure Description Number of subjects for association between screening resistance and virologic response as determined by treatment failure and OSS at screening. OSS categorized as 0, 1, 2, or ≥3 (maximum value of 6) and calculated as the sum of the net assessment of in vitro phenotypic and genotypic susceptibility using a binary scoring system (0= reduced susceptibility, 1=susceptible) for each antiretroviral agent in OBT. Higher scores indicate greater susceptibility.
Time Frame Screening, Week48  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS - as treated dual-tropic subjects. Missing values imputed as LOCF.

Reporting Groups
  Description
Maraviroc QD Maraviroc 150 mg by mouth (PO) once daily (QD) in combination with optimized background therapy (OBT) (3 to 6 drugs based on treatment history and resistance testing). The 150 mg QD arm = placebo drug in the morning and active drug in the evening.
Maraviroc BID Maraviroc 150 mg PO twice a day (BID) in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The 150 mg BID arm = active drug in the morning and evening.
Placebo Placebo BID in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The placebo arm = placebo drug in the morning and evening.

Measured Values
   Maraviroc QD   Maraviroc BID   Placebo 
Participants Analyzed 
[Units: Participants]
 57   52   58 
Number of Subjects With Treatment Failure at Week 48 by Overall Susceptibility Score (OSS) at Screening 
[Units: Particpants]
     
Scr score: 0   1   2   2 
Scr score: 1   19   11   15 
Scr score: 2   21   14   13 
Scr score: ≥3   15   24   27 
Scr score: missing   1   1   1 

No statistical analysis provided for Number of Subjects With Treatment Failure at Week 48 by Overall Susceptibility Score (OSS) at Screening



15.  Secondary:   Number of Subjects With Acquired Immunodeficiency Syndrome (AIDS)-Defining Opportunistic Illnesses (Analysis at Week 24)   [ Time Frame: Baseline through Week 24 ]

Measure Type Secondary
Measure Title Number of Subjects With Acquired Immunodeficiency Syndrome (AIDS)-Defining Opportunistic Illnesses (Analysis at Week 24)
Measure Description Number of subjects with AIDS-defining opportunistic illnesses based on investigator classification guided by a predefined list of clinical Category C Adverse Events per Center for Disease Control (CDC) HIV Classification System. Includes events occurring up to 7 days after last dose of study drug.
Time Frame Baseline through Week 24  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS - as randomized; N=number of subjects with Category C Adverse Events for maraviroc QD, maraviroc BID, and placebo, respectively. Week 48 results reflect subsequent updates to data originally reported at Week 24.

Reporting Groups
  Description
Maraviroc QD Maraviroc 150 mg by mouth (PO) once daily (QD) in combination with optimized background therapy (OBT) (3 to 6 drugs based on treatment history and resistance testing). The 150 mg QD arm = placebo drug in the morning and active drug in the evening.
Maraviroc BID Maraviroc 150 mg PO twice a day (BID) in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The 150 mg BID arm = active drug in the morning and evening.
Placebo Placebo BID in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The placebo arm = placebo drug in the morning and evening.

Measured Values
   Maraviroc QD   Maraviroc BID   Placebo 
Participants Analyzed 
[Units: Participants]
 63   61   62 
Number of Subjects With Acquired Immunodeficiency Syndrome (AIDS)-Defining Opportunistic Illnesses (Analysis at Week 24) 
[Units: Participants]
     
Candidiasis   0   0   1 
Cytomegalovirus chorioretinitis   1   0   0 
Herpes simplex   1   0   0 
Histoplasmosis   1   0   0 
Mycobacterium avium complex infection   1   0   0 
Oesophageal candidiasis   0   2   0 
Pneumocystis jiroveci pneumonia   3   1   0 
Pneumonia   0   0   1 
Encephalitis   0   0   1 

No statistical analysis provided for Number of Subjects With Acquired Immunodeficiency Syndrome (AIDS)-Defining Opportunistic Illnesses (Analysis at Week 24)



16.  Secondary:   Number of Subjects With Acquired Immunodeficiency Syndrome (AIDS)-Defining Opportunistic Illnesses (Analysis at Week 48)   [ Time Frame: Baseline through Week 48 ]

Measure Type Secondary
Measure Title Number of Subjects With Acquired Immunodeficiency Syndrome (AIDS)-Defining Opportunistic Illnesses (Analysis at Week 48)
Measure Description Number of subjects with AIDS-defining opportunistic illnesses based on investigator classification guided by a predefined list of clinical Category C Adverse Events per CDC HIV Classification System. Includes events occurring up to 7 days after last dose of study drug.
Time Frame Baseline through Week 48  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS - as randomized; N=number of subjects with Category C Adverse Events for maraviroc QD, maraviroc BID, and placebo, respectively. Week 48 results reflect subsequent updates to data originally reported at Week 24.

Reporting Groups
  Description
Maraviroc QD Maraviroc 150 mg by mouth (PO) once daily (QD) in combination with optimized background therapy (OBT) (3 to 6 drugs based on treatment history and resistance testing). The 150 mg QD arm = placebo drug in the morning and active drug in the evening.
Maraviroc BID Maraviroc 150 mg PO twice a day (BID) in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The 150 mg BID arm = active drug in the morning and evening.
Placebo Placebo BID in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The placebo arm = placebo drug in the morning and evening.

Measured Values
   Maraviroc QD   Maraviroc BID   Placebo 
Participants Analyzed 
[Units: Participants]
 63   61   62 
Number of Subjects With Acquired Immunodeficiency Syndrome (AIDS)-Defining Opportunistic Illnesses (Analysis at Week 48) 
[Units: Participants]
     
Candidiasis   0   1   1 
Cytomegalovirus chorioretinitis   1   0   0 
Histoplasmosis   1   0   0 
Oesophageal candidiasis   0   2   0 
Pneumococcal Sepsis   0   1   0 
Pneumocystis jiroveci pneumonia   3   0   0 
Pneumonia   0   1   0 
Encephalitis   0   0   1 

No statistical analysis provided for Number of Subjects With Acquired Immunodeficiency Syndrome (AIDS)-Defining Opportunistic Illnesses (Analysis at Week 48)




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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