Trial of Maraviroc (UK-427,857) in Combination With Zidovudine/Lamivudine Versus Efavirenz in Combination With Zidovudine/Lamivudine (MERIT)

This study has been completed.
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
ViiV Healthcare
ClinicalTrials.gov Identifier:
NCT00098293
First received: December 6, 2004
Last updated: August 7, 2013
Last verified: August 2013
Results First Received: July 9, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: HIV-1
Interventions: Drug: Maraviroc + Zidovudine/Lamivudine
Drug: Efavirenz + Zidovudine/Lamivudine
Drug: Maraviroc (UK-427,857) + Zidovudine/Lamivudine

  Participant Flow
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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
Data Safety Monitoring Board (DSMB) recommended termination of maraviroc once daily treatment after interim analysis at nominal week 16, 130 participants of 177 randomized were switched to open-label (OL) maraviroc twice daily.

Reporting Groups
  Description
Maraviroc Once Daily + CBV (DB) Maraviroc 300 milligram (mg) tablet orally once daily in the evening along with placebo matched to maraviroc 300 mg tablet orally once daily in the morning and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the double-blind (DB) phase prior to the termination of the treatment arm based on the recommendation of the DSMB following a planned interim analysis. DB phase nominally ended at last participant’s Week 96 visit.
Maraviroc Twice Daily + CBV (DB and OL) Maraviroc 300 mg tablet orally twice daily and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase. DB phase nominally ended at last participant’s Week 96 visit. Maraviroc 300 mg tablet orally twice daily co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the open-label (OL) phase. OL phase continued for at least 3 years after DB phase.
Efavirenz Once Daily + CBV (DB and OL) Placebo matched to maraviroc 300 mg tablet orally twice daily and efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase. DB phase nominally ended at last participant’s Week 96 visit. Efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the OL phase. OL phase continued for at least 3 years after DB phase.
Maraviroc Twice Daily + CBV (OL) Participants who received maraviroc 300 mg tablet orally once daily treatment during the DB phase and who were eligible based on safety criteria and virologic response, switched to OL maraviroc 300 mg tablet orally twice daily co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, following the DSMB recommendation to terminate the maraviroc once daily treatment arm after planned interim analysis. OL phase continued for at least 3 years after DB phase.
Maraviroc Twice Daily + CBV (SP) Participants who remained on mararviroc until their open-label phase End-of-Study visit and for whom maraviroc was commercially or otherwise unavailable entered an additional supplemental phase (SP) (initially planned for 6 months and subsequently extended for another 6 months) which consisted of study visits at 3-month intervals and received maraviroc 300 mg tablet orally twice daily co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily until maraviroc was commercially or otherwise available.

Participant Flow for 4 periods

Period 1:   Double-blind (DB) Phase
    Maraviroc Once Daily + CBV (DB)     Maraviroc Twice Daily + CBV (DB and OL)     Efavirenz Once Daily + CBV (DB and OL)     Maraviroc Twice Daily + CBV (OL)     Maraviroc Twice Daily + CBV (SP)  
STARTED     177     368     372     0     0  
Treated     174     360     361     0     0  
COMPLETED     0     202     202     0     0  
NOT COMPLETED     177     166     170     0     0  
Adverse Event                 14                 27                 60                 0                 0  
Pregnancy                 0                 7                 9                 0                 0  
Participant Defaulted                 11                 40                 36                 0                 0  
Lack of Efficacy                 11                 64                 30                 0                 0  
Death                 1                 2                 2                 0                 0  
Randomized, Not Treated                 3                 8                 11                 0                 0  
Protocol Violation                 2                 18                 22                 0                 0  
Terminated by sponsor                 135                 0                 0                 0                 0  

Period 2:   Between DB and OL Phase
    Maraviroc Once Daily + CBV (DB)     Maraviroc Twice Daily + CBV (DB and OL)     Efavirenz Once Daily + CBV (DB and OL)     Maraviroc Twice Daily + CBV (OL)     Maraviroc Twice Daily + CBV (SP)  
STARTED     0     202     202     0     0  
COMPLETED     0     202     199     0     0  
NOT COMPLETED     0     0     3     0     0  
Did Not Enter Open-label Phase                 0                 0                 3                 0                 0  

Period 3:   Open-label (OL) Phase
    Maraviroc Once Daily + CBV (DB)     Maraviroc Twice Daily + CBV (DB and OL)     Efavirenz Once Daily + CBV (DB and OL)     Maraviroc Twice Daily + CBV (OL)     Maraviroc Twice Daily + CBV (SP)  
STARTED     0     202     199     130     0  
COMPLETED     0     177     158     65     0  
NOT COMPLETED     0     25     41     65     0  
Adverse Event                 0                 3                 7                 6                 0  
Lack of Efficacy                 0                 7                 2                 20                 0  
Pregnancy                 0                 1                 0                 3                 0  
Protocol Violation                 0                 6                 13                 16                 0  
Participant Defaulted                 0                 6                 16                 20                 0  
Death                 0                 2                 3                 0                 0  

Period 4:   Supplemental Phase (SP)
    Maraviroc Once Daily + CBV (DB)     Maraviroc Twice Daily + CBV (DB and OL)     Efavirenz Once Daily + CBV (DB and OL)     Maraviroc Twice Daily + CBV (OL)     Maraviroc Twice Daily + CBV (SP)  
STARTED     0     0     0     0     127  
COMPLETED     0     0     0     0     94  
NOT COMPLETED     0     0     0     0     33  
Death                 0                 0                 0                 0                 1  
Lost to Follow-up                 0                 0                 0                 0                 2  
Withdrawal by Subject                 0                 0                 0                 0                 8  
Unspecified                 0                 0                 0                 0                 22  



  Baseline Characteristics
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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 Once Daily + CBV (DB) Maraviroc 300 milligram (mg) tablet orally once daily in the evening along with placebo matched to maraviroc 300 mg tablet orally once daily in the morning and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the double-blind (DB) phase prior to the termination of the treatment arm based on the recommendation of the DSMB following a planned interim analysis. DB phase nominally ended at last participant’s Week 96 visit.
Maraviroc Twice Daily + CBV (DB and OL) Maraviroc 300 mg tablet orally twice daily and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase. DB phase nominally ended at last participant’s Week 96 visit. Maraviroc 300 mg tablet orally twice daily co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the open-label (OL) phase. OL phase continued for at least 3 years after DB phase.
Efavirenz Once Daily + CBV (DB and OL) Placebo matched to maraviroc 300 mg tablet orally twice daily and efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, up to week 96 in DB phase. Efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily from Week 97 up to Week 240 in open-label (OL) phase.
Total Total of all reporting groups

Baseline Measures
    Maraviroc Once Daily + CBV (DB)     Maraviroc Twice Daily + CBV (DB and OL)     Efavirenz Once Daily + CBV (DB and OL)     Total  
Number of Participants  
[units: participants]
  174     360     361     895  
Age, Customized  
[units: participants]
       
Less than 18 years     0     0     0     0  
18 to 24 years     17     24     25     66  
25 to 34 years     47     147     120     314  
35 to 44 years     73     117     141     331  
45 to 54 years     29     56     55     140  
55 to 64 years     7     14     15     36  
Greater than or equal to 65 years     1     2     5     8  
Gender  
[units: participants]
       
Female     44     104     102     250  
Male     130     256     259     645  



  Outcome Measures
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1.  Primary:   Percentage of Participants With Viral Load of Less Than 400 Copies/Milliliter [Copies/mL] and Less Than 50 Copies/mL of Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) at Week 48 for Full Analysis Set (FAS) Population   [ Time Frame: Week 48 ]

Measure Type Primary
Measure Title Percentage of Participants With Viral Load of Less Than 400 Copies/Milliliter [Copies/mL] and Less Than 50 Copies/mL of Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) at Week 48 for Full Analysis Set (FAS) Population
Measure Description No text entered.
Time Frame Week 48  
Safety Issue No  

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 population included all the randomized participants who had taken at least 1 dose of the study medication. Missing data (MD) imputed as failure (F); that is, participants with missing data classified as not achieving the viral load criterion (MD=F).

Reporting Groups
  Description
Maraviroc Once Daily + CBV (DB), Then Twice Daily + CBV (OL) Maraviroc 300 milligram (mg) tablet orally once daily in the evening along with placebo matched to maraviroc 300 mg tablet orally once daily in the morning and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase prior to the termination of the treatment arm based on the recommendation of the DSMB following a planned interim analysis. Eligible participants then switched to open-label maraviroc 300 mg tablet orally twice daily co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily for the remainder of the study.
Maraviroc Twice Daily + CBV (DB) Maraviroc 300 mg tablet orally twice daily and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.
Efavirenz Once Daily + CBV (DB) Placebo matched to maraviroc 300 mg tablet orally twice daily and efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.

Measured Values
    Maraviroc Once Daily + CBV (DB), Then Twice Daily + CBV (OL)     Maraviroc Twice Daily + CBV (DB)     Efavirenz Once Daily + CBV (DB)  
Number of Participants Analyzed  
[units: participants]
  174     360     361  
Percentage of Participants With Viral Load of Less Than 400 Copies/Milliliter [Copies/mL] and Less Than 50 Copies/mL of Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) at Week 48 for Full Analysis Set (FAS) Population  
[units: Percentage of participants]
     
Less than 400 copies/mL     61.5     70.6     73.1  
Less than 50 copies/mL     55.8     65.3     69.3  


Statistical Analysis 1 for Percentage of Participants With Viral Load of Less Than 400 Copies/Milliliter [Copies/mL] and Less Than 50 Copies/mL of Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) at Week 48 for Full Analysis Set (FAS) Population
Groups [1] Maraviroc Twice Daily + CBV (DB) vs. Efavirenz Once Daily + CBV (DB)
Non-Inferiority/Equivalence Test [2] Yes
Difference in Percentage [3] -3.0
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Less than 400 copies/mL: Treatment difference in percentages stratified by randomization strata (screening viral load and geographic region) was presented along with the lower bound of the 1-sided 97.5% confidence interval (CI) based on the normal approximation to the binomial distribution. Positive value would favor maraviroc. Step down procedure used to control for multiple comparisons.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Non-inferiority was to be concluded if the lower bound of the 1-sided 97.5% CI was greater than (>) -10%.
[3] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Percentage of Participants With Viral Load of Less Than 400 Copies/Milliliter [Copies/mL] and Less Than 50 Copies/mL of Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) at Week 48 for Full Analysis Set (FAS) Population
Groups [1] Maraviroc Twice Daily + CBV (DB) vs. Efavirenz Once Daily + CBV (DB)
Non-Inferiority/Equivalence Test [2] Yes
Difference in Percentage [3] -4.2
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Less than 50 copies/mL: Treatment difference in percentages stratified by randomization strata (screening viral load and geographic region) was presented along with the lower bound of the 1-sided 97.5% CI based on the normal approximation to the binomial distribution. Positive value would favor maraviroc. Step down procedure used to control for multiple comparisons.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Non-inferiority was to be concluded if the lower bound of the 1-sided 97.5% CI was > -10%.
[3] Other relevant estimation information:
  No text entered.



2.  Primary:   Percentage of Participants With Viral Load of Less Than 400 Copies/mL and Less Than 50 Copies/mL of HIV-1 RNA at Week 48 for Per Protocol (PP) Population   [ Time Frame: Week 48 ]

Measure Type Primary
Measure Title Percentage of Participants With Viral Load of Less Than 400 Copies/mL and Less Than 50 Copies/mL of HIV-1 RNA at Week 48 for Per Protocol (PP) Population
Measure Description Percentage of participants with viral load of less than 400 copies/mL and less than 50 copies/mL of HIV-1 RNA were not analyzed for participants originally randomized to maraviroc once daily arm since after termination, focus was shifted from efficacy and safety to only safety as reflected in the abbreviated set of efficacy measures noted in the amended planned analysis.
Time Frame Week 48  
Safety Issue No  

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.
Per protocol (PP) population included all randomized participants who had taken at least 1 dose of study medication, were treated for at least 14 days or discontinued before this time due to treatment failure, were >80% compliant with randomized treatment and had no violation of any inclusion or exclusion criteria, which affected efficacy. MD=F.

Reporting Groups
  Description
Maraviroc Twice Daily + CBV (DB) Maraviroc 300 mg tablet orally twice daily and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.
Efavirenz Once Daily + CBV (DB) Placebo matched to maraviroc 300 mg tablet orally twice daily and efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.

Measured Values
    Maraviroc Twice Daily + CBV (DB)     Efavirenz Once Daily + CBV (DB)  
Number of Participants Analyzed  
[units: participants]
  360     361  
Percentage of Participants With Viral Load of Less Than 400 Copies/mL and Less Than 50 Copies/mL of HIV-1 RNA at Week 48 for Per Protocol (PP) Population  
[units: Percentage of participants]
   
Less than 400 copies/mL     75.00     78.27  
Less than 50 copies/mL     70.00     74.44  


Statistical Analysis 1 for Percentage of Participants With Viral Load of Less Than 400 Copies/mL and Less Than 50 Copies/mL of HIV-1 RNA at Week 48 for Per Protocol (PP) Population
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Difference in Percentage [3] -4.1
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Less than 400 copies/mL: Treatment difference in percentage stratified by randomization strata (screening viral load and geographic region) was presented along with the lower bound of the 1-sided 97.5% CI based on the normal approximation to the binomial distribution. Positive value would favor maraviroc. Step down procedure used to control for multiple comparisons.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Non-inferiority was to be concluded if the lower bound of the 1-sided 97.5% CI was > -10%.
[3] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Percentage of Participants With Viral Load of Less Than 400 Copies/mL and Less Than 50 Copies/mL of HIV-1 RNA at Week 48 for Per Protocol (PP) Population
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Difference in Percentage [3] -4.4
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Less than 50 copies/mL: Treatment difference in percentage stratified by randomization strata (screening viral load and geographic region) was presented along with the lower bound of the 1-sided 97.5% CI based on the normal approximation to the binomial distribution. Positive value would favor maraviroc. Step down procedure used to control for multiple comparisons.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Non-inferiority was to be concluded if the lower bound of the 1-sided 97.5% CI was > -10%.
[3] Other relevant estimation information:
  No text entered.



3.  Secondary:   Percentage of Participants With HIV-1 RNA Levels of Less Than 400 Copies/mL and Less Than 50 Copies/mL at Week 48 Analyzed Using Logistic Regression   [ Time Frame: Week 48 ]

Measure Type Secondary
Measure Title Percentage of Participants With HIV-1 RNA Levels of Less Than 400 Copies/mL and Less Than 50 Copies/mL at Week 48 Analyzed Using Logistic Regression
Measure Description No text entered.
Time Frame Week 48  
Safety Issue No  

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 population included all the randomized participants who had taken at least 1 dose of the study medication. Missing data (MD) imputed as failure (F); that is, participants with missing data classified as not achieving the viral load criterion (MD=F).

Reporting Groups
  Description
Maraviroc Once Daily + CBV (DB), Then Twice Daily + CBV (OL) Maraviroc 300 milligram (mg) tablet orally once daily in the evening along with placebo matched to maraviroc 300 mg tablet orally once daily in the morning and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase prior to the termination of the treatment arm based on the recommendation of the DSMB following a planned interim analysis. Eligible participants then switched to open-label maraviroc 300 mg tablet orally twice daily co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily for the remainder of the study.
Maraviroc Twice Daily + CBV (DB) Maraviroc 300 mg tablet orally twice daily and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.
Efavirenz Once Daily + CBV (DB) Placebo matched to maraviroc 300 mg tablet orally twice daily and efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.

Measured Values
    Maraviroc Once Daily + CBV (DB), Then Twice Daily + CBV (OL)     Maraviroc Twice Daily + CBV (DB)     Efavirenz Once Daily + CBV (DB)  
Number of Participants Analyzed  
[units: participants]
  174     360     361  
Percentage of Participants With HIV-1 RNA Levels of Less Than 400 Copies/mL and Less Than 50 Copies/mL at Week 48 Analyzed Using Logistic Regression  
[units: Percentage of participants]
     
Less than 400 copies/mL     61.5     70.6     73.1  
Less than 50 copies/mL     55.8     65.3     69.3  


Statistical Analysis 1 for Percentage of Participants With HIV-1 RNA Levels of Less Than 400 Copies/mL and Less Than 50 Copies/mL at Week 48 Analyzed Using Logistic Regression
Groups [1] Maraviroc Twice Daily + CBV (DB) vs. Efavirenz Once Daily + CBV (DB)
Method [2] Regression, Logistic
P Value [3] 0.4485
Odds Ratio (OR) [4] 0.88
95% Confidence Interval ( 0.64 to 1.22 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Less than 400 copies/mL: Two-sided 95% CI was presented for the odds ratio between treatment groups. CIs were calculated using the Wald-approximation. Logistic model with treatment, screening HIV concentrations (<100,000 or >=100,000), geographic region (Northern or Southern Hemisphere) as covariates was used. Odds ratio > 1 would favor maraviroc.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Percentage of Participants With HIV-1 RNA Levels of Less Than 400 Copies/mL and Less Than 50 Copies/mL at Week 48 Analyzed Using Logistic Regression
Groups [1] Maraviroc Twice Daily + CBV (DB) vs. Efavirenz Once Daily + CBV (DB)
Method [2] Regression, Logistic
P Value [3] 0.2724
Odds Ratio (OR) [4] 0.84
95% Confidence Interval ( 0.61 to 1.15 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Less than 50 copies/mL: Two-sided 95% CI was presented for the odds ratio between treatment groups. CIs were calculated using the Wald-approximation. Logistic model with treatment, screening HIV concentrations (<100,000 or >=100,000), geographic region (Northern or Southern Hemisphere) as covariates were used. Odds ratio > 1 would favor maraviroc.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



4.  Secondary:   Percentage of Participants With HIV-1 RNA Levels of Less Than 400 Copies/mL and Less Than 50 Copies/mL at Week 96 Analyzed Using Logistic Regression   [ Time Frame: Week 96 ]

Measure Type Secondary
Measure Title Percentage of Participants With HIV-1 RNA Levels of Less Than 400 Copies/mL and Less Than 50 Copies/mL at Week 96 Analyzed Using Logistic Regression
Measure Description No text entered.
Time Frame Week 96  
Safety Issue No  

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 population included all the randomized participants who had taken at least 1 dose of the study medication. Missing data (MD) imputed as failure (F); that is, participants with missing data classified as not achieving the viral load criterion (MD=F).

Reporting Groups
  Description
Maraviroc Once Daily + CBV (DB), Then Twice Daily + CBV (OL) Maraviroc 300 milligram (mg) tablet orally once daily in the evening along with placebo matched to maraviroc 300 mg tablet orally once daily in the morning and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase prior to the termination of the treatment arm based on the recommendation of the DSMB following a planned interim analysis. Eligible participants then switched to open-label maraviroc 300 mg tablet orally twice daily co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily for the remainder of the study.
Maraviroc Twice Daily + CBV (DB) Maraviroc 300 mg tablet orally twice daily and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.
Efavirenz Once Daily + CBV (DB) Placebo matched to maraviroc 300 mg tablet orally twice daily and efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.

Measured Values
    Maraviroc Once Daily + CBV (DB), Then Twice Daily + CBV (OL)     Maraviroc Twice Daily + CBV (DB)     Efavirenz Once Daily + CBV (DB)  
Number of Participants Analyzed  
[units: participants]
  174     360     361  
Percentage of Participants With HIV-1 RNA Levels of Less Than 400 Copies/mL and Less Than 50 Copies/mL at Week 96 Analyzed Using Logistic Regression  
[units: Percentage of participants]
     
Less than 400 copies/mL     52.9     61.4     64.5  
Less than 50 copies/mL     48.3     56.9     62.6  


Statistical Analysis 1 for Percentage of Participants With HIV-1 RNA Levels of Less Than 400 Copies/mL and Less Than 50 Copies/mL at Week 96 Analyzed Using Logistic Regression
Groups [1] Maraviroc Twice Daily + CBV (DB) vs. Efavirenz Once Daily + CBV (DB)
Method [2] Regression, Logistic
P Value [3] 0.3943
Odds Ratio (OR) [4] 0.88
95% Confidence Interval ( 0.65 to 1.19 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Less than 400 copies/mL: Two-sided 95% CI was presented for the odds ratio between treatment groups. CIs were calculated using the Wald-approximation. Logistic model with treatment, screening HIV concentrations (<100,000 or >=100,000), geographic region (Northern or Southern Hemisphere) as covariates were used. Odds ratio > 1 would favor maraviroc.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Percentage of Participants With HIV-1 RNA Levels of Less Than 400 Copies/mL and Less Than 50 Copies/mL at Week 96 Analyzed Using Logistic Regression
Groups [1] Maraviroc Twice Daily + CBV (DB) vs. Efavirenz Once Daily + CBV (DB)
Method [2] Regression, Logistic
P Value [3] 0.1289
Odds Ratio (OR) [4] 0.79
95% Confidence Interval ( 0.59 to 1.07 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Less than 50 copies/mL: Two-sided 95% CI was presented for the odds ratio between treatment groups. CIs were calculated using the Wald-approximation. Logistic model with treatment, screening HIV concentrations (<100,000 or >=100,000), geographic region (Northern or Southern Hemisphere) as covariates were used. Odds ratio > 1 would favor maraviroc.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



5.  Secondary:   Change From Baseline in Log 10-transformed Plasma Viral Load (HIV-1 RNA) Levels at Week 48 and 96   [ Time Frame: Baseline, Week 48, Week 96 ]

Measure Type Secondary
Measure Title Change From Baseline in Log 10-transformed Plasma Viral Load (HIV-1 RNA) Levels at Week 48 and 96
Measure Description Change from baseline in log 10-transformed plasma viral load (HIV-1 RNA) levels (log10 copies/mL). Baseline value calculated as average of pre-dose measurements collected at screening, randomization, and immediately pre-dose.
Time Frame Baseline, Week 48, Week 96  
Safety Issue No  

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 population. Missing values for viral load at week 48 and 96 were imputed as baseline value for participants who discontinued and as last observation carried forward (LOCF) for participants who did not discontinue for maraviroc twice daily and efavirenz once daily arm and as LOCF for participants randomized to maraviroc once daily arm.

Reporting Groups
  Description
Maraviroc Once Daily + CBV (DB), Then Twice Daily + CBV (OL) Maraviroc 300 milligram (mg) tablet orally once daily in the evening along with placebo matched to maraviroc 300 mg tablet orally once daily in the morning and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase prior to the termination of the treatment arm based on the recommendation of the DSMB following a planned interim analysis. Eligible participants then switched to open-label maraviroc 300 mg tablet orally twice daily co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily for the remainder of the study.
Maraviroc Twice Daily + CBV (DB) Maraviroc 300 mg tablet orally twice daily and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.
Efavirenz Once Daily + CBV (DB) Placebo matched to maraviroc 300 mg tablet orally twice daily and efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.

Measured Values
    Maraviroc Once Daily + CBV (DB), Then Twice Daily + CBV (OL)     Maraviroc Twice Daily + CBV (DB)     Efavirenz Once Daily + CBV (DB)  
Number of Participants Analyzed  
[units: participants]
  174     360     361  
Change From Baseline in Log 10-transformed Plasma Viral Load (HIV-1 RNA) Levels at Week 48 and 96  
[units: log10 copies/mL]
Mean ± Standard Deviation
     
Baseline     4.899  ± 0.6273     4.851  ± 0.6511     4.857  ± 0.6156  
Change at Week 48     -2.665  ± 0.9454     -2.240  ± 1.484     -2.347  ± 1.455  
Change at Week 96     -2.565  ± 0.9731     -1.961  ± 1.575     -2.053  ± 1.564  


Statistical Analysis 1 for Change From Baseline in Log 10-transformed Plasma Viral Load (HIV-1 RNA) Levels at Week 48 and 96
Groups [1] Maraviroc Twice Daily + CBV (DB) vs. Efavirenz Once Daily + CBV (DB)
Method [2] ANCOVA
P Value [3] 0.2741
LS Mean Difference [4] 0.118
Standard Error of the mean ± 0.1077
95% Confidence Interval ( -0.094 to 0.329 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Change at week 48: P-value was calculated using Analysis of Covariance (ANCOVA) with the model including treatment arm and, as covariates, the randomization strata (screening viral load and geographic region). The difference between the treatment least squares means (LS means) adjusted for the covariates was presented in addition to 2-sided 95% CI. Negative value would favor maraviroc.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Change From Baseline in Log 10-transformed Plasma Viral Load (HIV-1 RNA) Levels at Week 48 and 96
Groups [1] Maraviroc Twice Daily + CBV (DB) vs. Efavirenz Once Daily + CBV (DB)
Method [2] ANCOVA
P Value [3] 0.3899
LS Mean Difference [4] 0.100
Standard Error of the mean ± 0.1162
95% Confidence Interval ( -0.128 to 0.328 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Change at week 96: P-value was calculated using ANCOVA with the model including treatment arm and, as covariates, the randomization strata (screening viral load and geographic region). The difference between the treatment LS means adjusted for the covariates was presented in addition to 2-sided 95% CI. Negative value would favor maraviroc.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



6.  Secondary:   Time-Averaged Difference (TAD) in log10-transformed HIV-1 RNA Levels   [ Time Frame: Baseline up to Week 48 and Week 96 ]

Measure Type Secondary
Measure Title Time-Averaged Difference (TAD) in log10-transformed HIV-1 RNA Levels
Measure Description TAD from baseline was calculated as area under the curve (AUC) of HIV-1 RNA load (log10 copies/mL) divided by time period minus baseline HIV-1 RNA load (log10 copies/mL). Baseline value calculated as average of pre-dose measurements collected at screening, randomization, and immediately pre-dose. Data not analyzed for participants originally randomized to maraviroc once daily arm since after termination, focus was shifted from efficacy and safety to only safety as reflected in the abbreviated set of efficacy measures noted in the amended planned analysis.
Time Frame Baseline up to Week 48 and Week 96  
Safety Issue No  

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 population included all the randomized participants who had taken at least 1 dose of the study medication. TAD imputed as 0 for participants who discontinued. TAD calculated using the last non-missing value prior to the analysis time point for participants with a missing value at the analysis time point but who had not discontinued.

Reporting Groups
  Description
Maraviroc Twice Daily + CBV (DB) Maraviroc 300 mg tablet orally twice daily and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.
Efavirenz Once Daily + CBV (DB) Placebo matched to maraviroc 300 mg tablet orally twice daily and efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.

Measured Values
    Maraviroc Twice Daily + CBV (DB)     Efavirenz Once Daily + CBV (DB)  
Number of Participants Analyzed  
[units: participants]
  360     361  
Time-Averaged Difference (TAD) in log10-transformed HIV-1 RNA Levels  
[units: log10 copies/mL]
Least Squares Mean ± Standard Error
   
Week 48     -2.152  ± 0.0713     -2.262  ± 0.0714  
Week 96     -1.945  ± 0.0798     -2.034  ± 0.0800  


Statistical Analysis 1 for Time-Averaged Difference (TAD) in log10-transformed HIV-1 RNA Levels
Groups [1] All groups
Method [2] ANCOVA
P Value [3] 0.2693
LS Mean Difference [4] 0.111
Standard Error of the mean ± 0.1002
95% Confidence Interval ( -0.086 to 0.307 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Week 48: P-value was calculated using ANCOVA with the model including treatment arm and, as covariates, the randomization strata (screening viral load and geographic region). The difference between the treatment LS means adjusted for the covariates was presented in addition to 2-sided 95% CI. Negative value would favor maraviroc.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Time-Averaged Difference (TAD) in log10-transformed HIV-1 RNA Levels
Groups [1] All groups
Method [2] ANCOVA
P Value [3] 0.4270
LS Mean Difference [4] 0.089
Standard Error of the mean ± 0.1121
95% Confidence Interval ( -0.131 to 0.309 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Week 96: P-value was calculated using ANCOVA with the model including treatment arm and, as covariates, the randomization strata (screening viral load and geographic region). The difference between the treatment LS means adjusted for the covariates was presented in addition to 2-sided 95% CI. Negative value would favor maraviroc.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



7.  Secondary:   Change From Baseline in Lymphocyte Cluster of Differentiation 4 (CD4) Count at Week 48 and 96   [ Time Frame: Baseline, Week 48, Week 96 ]

Measure Type Secondary
Measure Title Change From Baseline in Lymphocyte Cluster of Differentiation 4 (CD4) Count at Week 48 and 96
Measure Description Baseline value calculated as the average of pre-dose measurements collected at screening and immediately pre-dose.
Time Frame Baseline, Week 48, Week 96  
Safety Issue No  

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 population included all the randomized participants who had taken at least 1 dose of the study medication. 'N' (number of participants analyzed) signifies participants evaluable for this measure. Missing values were imputed using LOCF.

Reporting Groups
  Description
Maraviroc Once Daily + CBV (DB), Then Twice Daily + CBV (OL) Maraviroc 300 milligram (mg) tablet orally once daily in the evening along with placebo matched to maraviroc 300 mg tablet orally once daily in the morning and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase prior to the termination of the treatment arm based on the recommendation of the DSMB following a planned interim analysis. Eligible participants then switched to open-label maraviroc 300 mg tablet orally twice daily co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily for the remainder of the study.
Maraviroc Twice Daily + CBV (DB) Maraviroc 300 mg tablet orally twice daily and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.
Efavirenz Once Daily + CBV (DB) Placebo matched to maraviroc 300 mg tablet orally twice daily and efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.

Measured Values
    Maraviroc Once Daily + CBV (DB), Then Twice Daily + CBV (OL)     Maraviroc Twice Daily + CBV (DB)     Efavirenz Once Daily + CBV (DB)  
Number of Participants Analyzed  
[units: participants]
  174     360     360  
Change From Baseline in Lymphocyte Cluster of Differentiation 4 (CD4) Count at Week 48 and 96  
[units: cells per microliter (cells/µL)]
Mean ± Standard Deviation
     
Baseline     274.1  ± 175.45     264.70  ± 153.508     271.87  ± 133.491  
Change at Week 48     172.50  ± 205.561     169.53  ± 134.409     143.52  ± 124.931  
Change at Week 96     183.75  ± 166.454     206.31  ± 152.682     171.50  ± 149.163  


Statistical Analysis 1 for Change From Baseline in Lymphocyte Cluster of Differentiation 4 (CD4) Count at Week 48 and 96
Groups [1] Maraviroc Twice Daily + CBV (DB) vs. Efavirenz Once Daily + CBV (DB)
Method [2] ANCOVA
P Value [3] 0.0075
LS Mean Difference [4] 26.34
Standard Error of the mean ± 9.827
95% Confidence Interval ( 7.04 to 45.63 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Change at Week 48: P-value was calculated using ANCOVA with the model including treatment arm and, as covariates, baseline CD4 count and the randomization strata (screening viral load and geographic region). The difference between the treatment LS means adjusted for the covariates was presented in addition to 2-sided 95% CI. Positive value would favor maraviroc.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Change From Baseline in Lymphocyte Cluster of Differentiation 4 (CD4) Count at Week 48 and 96
Groups [1] Maraviroc Twice Daily + CBV (DB) vs. Efavirenz Once Daily + CBV (DB)
Method [2] ANCOVA
P Value [3] 0.0020
LS Mean Difference [4] 35.44
Standard Error of the mean ± 11.419
95% Confidence Interval ( 13.02 to 57.86 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Change at Week 96: P-value was calculated using ANCOVA with the model including treatment arm and, as covariates, baseline CD4 count and the randomization strata (screening viral load and geographic region). The difference between the treatment LS means adjusted for the covariates was presented in addition to 2-sided 95% CI. Positive value would favor maraviroc.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



8.  Secondary:   Change From Baseline in Lymphocyte Cluster of Differentiation 8 (CD8) Count at Week 48 and 96   [ Time Frame: Baseline, Week 48, Week 96 ]

Measure Type Secondary
Measure Title Change From Baseline in Lymphocyte Cluster of Differentiation 8 (CD8) Count at Week 48 and 96
Measure Description Baseline value calculated as the average of pre-dose measurements collected at screening and immediately pre-dose. Change from baseline in lymphocyte CD8 count at Week 48 and 96 was not analyzed for participants originally randomized to maraviroc once daily arm since after termination, focus was shifted from efficacy and safety to only safety as reflected in the abbreviated set of efficacy measures noted in the amended planned analysis.
Time Frame Baseline, Week 48, Week 96  
Safety Issue No  

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 population included all the randomized participants who had taken at least 1 dose of the study medication. 'N' (number of participants analyzed) signifies participants evaluable for this measure. Missing values were imputed using LOCF.

Reporting Groups
  Description
Maraviroc Twice Daily + CBV (DB) Maraviroc 300 mg tablet orally twice daily and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.
Efavirenz Once Daily + CBV (DB) Placebo matched to maraviroc 300 mg tablet orally twice daily and efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.

Measured Values
    Maraviroc Twice Daily + CBV (DB)     Efavirenz Once Daily + CBV (DB)  
Number of Participants Analyzed  
[units: participants]
  360     360  
Change From Baseline in Lymphocyte Cluster of Differentiation 8 (CD8) Count at Week 48 and 96  
[units: cells/µL]
Mean ± Standard Deviation
   
Baseline     938.80  ± 503.392     935.78  ± 476.607  
Change at Week 48     38.34  ± 397.503     -126.83  ± 374.494  
Change at Week 96     20.74  ± 412.081     -150.27  ± 389.996  


Statistical Analysis 1 for Change From Baseline in Lymphocyte Cluster of Differentiation 8 (CD8) Count at Week 48 and 96
Groups [1] All groups
Method [2] ANCOVA
P Value [3] <0.0001
LS Mean Difference [4] 166.29
Standard Error of the mean ± 25.040
95% Confidence Interval ( 117.13 to 215.46 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Change at Week 48: P-value was calculated using ANCOVA with the model including treatment arm and, as covariates, baseline CD8 count and the randomization strata (screening viral load and geographic region). The difference between the treatment LS means adjusted for the covariates was presented in addition to 2-sided 95% CI. Positive value would favor maraviroc.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Change From Baseline in Lymphocyte Cluster of Differentiation 8 (CD8) Count at Week 48 and 96
Groups [1] All groups
Method [2] ANCOVA
P Value [3] <0.0001
LS Mean Difference [4] 172.22
Standard Error of the mean ± 25.471
95% Confidence Interval ( 122.21 to 222.23 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Change at Week 96: P-value was calculated using ANCOVA with the model including treatment arm and, as covariates, baseline CD8 count and the randomization strata (screening viral load and geographic region). The difference between the treatment LS means adjusted for the covariates was presented in addition to 2-sided 95% CI. Positive value would favor maraviroc.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



9.  Secondary:   Time to Virologic Failure   [ Time Frame: Week 48, Week 96 ]

Measure Type Secondary
Measure Title Time to Virologic Failure
Measure Description Time to virologic failure based on observed HIV-1 RNA levels and failure events (death;permanent discontinuation of drug;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 events or last available visit;at time of earliest event if level <400 copies/mL(2 consecutive visits);failure if level >=400 copies/mL(2 consecutive visits) or 1 visit >=400 copies/mL followed by permanent discontinuation of drug or LTFU.
Time Frame Week 48, Week 96  
Safety Issue No  

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 population; Data not analyzed for participants originally randomized to maraviroc once daily arm since after termination, focus was shifted from efficacy and safety to only safety as reflected in the abbreviated set of efficacy measures noted in the amended planned analysis.

Reporting Groups
  Description
Maraviroc Twice Daily + CBV (DB) Maraviroc 300 mg tablet orally twice daily and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.
Efavirenz Once Daily + CBV (DB) Placebo matched to maraviroc 300 mg tablet orally twice daily and efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.

Measured Values
    Maraviroc Twice Daily + CBV (DB)     Efavirenz Once Daily + CBV (DB)  
Number of Participants Analyzed  
[units: participants]
  360     361  
Time to Virologic Failure  
[units: days]
Median ( 95% Confidence Interval )
   
Week 48     NA  
  ( 354 to NA ) [1]
  NA  
  ( 364 to NA ) [1]
Week 96     NA  
  ( NA to NA ) [2]
  NA  
  ( 691 to NA ) [1]
[1] Median was not estimable because less than 50% of the participants experienced virological failure; upper confidence limit not estimable because the empirical distribution of the data rendered the algorithmic formula non-calculable.
[2] Median was not estimable because less than 50% of the participants experienced virological failure; confidence limits not estimable because the empirical distribution of the data rendered the algorithmic formula non-calculable.


Statistical Analysis 1 for Time to Virologic Failure
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.5874
Hazard Ratio (HR) [4] 1.10
95% Confidence Interval ( 0.83 to 1.45 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Week 48: P-value was calculated using Log rank test controlling for the effect of the randomization strata. Hazard ratio was calculated by fitting a Cox proportional hazards model including treatment group and the two randomization strata, HIV-1 RNA at screening and geographic region. Hazard ratio < 1 would favor maraviroc.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Time to Virologic Failure
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.4811
Hazard Ratio (HR) [4] 1.10
95% Confidence Interval ( 0.86 to 1.40 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Week 96: P-value was calculated using Log rank test controlling for the effect of the randomization strata. Hazard ratio was calculated by fitting a Cox proportional hazards model including treatment group and the two randomization strata, HIV-1 RNA at screening and geographic region. Hazard ratio < 1 would favor maraviroc.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



10.  Secondary:   Number of Participants Per Tropism Status at Baseline and at the Time of Treatment Failure Through Week 48   [ Time Frame: Baseline, time of failure through Week 48 ]

Measure Type Secondary
Measure Title Number of Participants Per Tropism Status at Baseline and at the Time of Treatment Failure Through Week 48
Measure Description Number of participants per tropism status (C-X-C chemokine receptor 5 {CCR5} [R5], C-X-C chemokine receptor type 4 {CXCR4} [X4], Dual/mixed [DM], or Non-reportable/Non-phenotypable [NR/NP]) at baseline and time of treatment failure analyzed through week 48 visit. Treatment failure: discontinuation due to insufficient clinical response. Tropism result was censored for participants with viral load <500 copies/mL at time of treatment failure categorized as below lower limit of quantification (BLQ). The assessment for time of treatment failure was defined as last on treatment assessment.
Time Frame Baseline, time of failure through Week 48  
Safety Issue No  

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 population included all the randomized participants who had taken at least 1 dose of the study medication. ‘N’ (number of participants analyzed) is signifying those participants who experienced treatment failure, defined as discontinuation due to insufficient response and had tropism assessment at baseline.

Reporting Groups
  Description
Maraviroc Once Daily + CBV (DB), Then Twice Daily + CBV (OL) Maraviroc 300 milligram (mg) tablet orally once daily in the evening along with placebo matched to maraviroc 300 mg tablet orally once daily in the morning and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase prior to the termination of the treatment arm based on the recommendation of the DSMB following a planned interim analysis. Eligible participants then switched to open-label maraviroc 300 mg tablet orally twice daily co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily for the remainder of the study.
Maraviroc Twice Daily + CBV (DB) Maraviroc 300 mg tablet orally twice daily and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.
Efavirenz Once Daily + CBV (DB) Placebo matched to maraviroc 300 mg tablet orally twice daily and efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.

Measured Values
    Maraviroc Once Daily + CBV (DB), Then Twice Daily + CBV (OL)     Maraviroc Twice Daily + CBV (DB)     Efavirenz Once Daily + CBV (DB)  
Number of Participants Analyzed  
[units: participants]
  20     42     15  
Number of Participants Per Tropism Status at Baseline and at the Time of Treatment Failure Through Week 48  
[units: participants]
     
Baseline: R5; Treatment failure: R5     5     11     6  
Baseline: R5; Treatment failure: X4     0     0     0  
Baseline: R5; Treatment failure: DM     3     10     0  
Baseline: R5; Treatment failure: NR/NP     5     5     4  
Baseline: DM; Treatment failure: R5     0     1     0  
Baseline: DM; Treatment failure: X4     0     2     0  
Baseline: DM; Treatment failure: DM     5     4     0  
Baseline: DM; Treatment failure: NR/NP     0     0     0  

No statistical analysis provided for Number of Participants Per Tropism Status at Baseline and at the Time of Treatment Failure Through Week 48



11.  Secondary:   Number of Participants Per Tropism Status at Baseline and at the Time of Treatment Failure Through Week 96   [ Time Frame: Baseline, time of failure through Week 96 ]

Measure Type Secondary
Measure Title Number of Participants Per Tropism Status at Baseline and at the Time of Treatment Failure Through Week 96
Measure Description Number of participants per tropism status (R5, X4, DM, or NR/NP) at baseline and time of treatment failure analyzed through week 96 visit. Treatment failure defined as insufficient clinical response. Tropism result was censored for participants with viral load <500 copies/mL at time of treatment failure categorized as BLQ. The assessment for time of treatment failure was defined as last on treatment assessment.
Time Frame Baseline, time of failure through Week 96  
Safety Issue No  

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 population included all the randomized participants who had taken at least 1 dose of the study medication. ‘N’ (number of participants analyzed) is signifying those participants who experienced treatment failure, defined as discontinuation due to insufficient response and had tropism assessment at baseline.

Reporting Groups
  Description
Maraviroc Once Daily + CBV (DB), Then Twice Daily + CBV (OL) Maraviroc 300 milligram (mg) tablet orally once daily in the evening along with placebo matched to maraviroc 300 mg tablet orally once daily in the morning and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase prior to the termination of the treatment arm based on the recommendation of the DSMB following a planned interim analysis. Eligible participants then switched to open-label maraviroc 300 mg tablet orally twice daily co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily for the remainder of the study.
Maraviroc Twice Daily + CBV (DB) Maraviroc 300 mg tablet orally twice daily and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.
Efavirenz Once Daily + CBV (DB) Placebo matched to maraviroc 300 mg tablet orally twice daily and efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.

Measured Values
    Maraviroc Once Daily + CBV (DB), Then Twice Daily + CBV (OL)     Maraviroc Twice Daily + CBV (DB)     Efavirenz Once Daily + CBV (DB)  
Number of Participants Analyzed  
[units: participants]
  27     54     23  
Number of Participants Per Tropism Status at Baseline and at the Time of Treatment Failure Through Week 96  
[units: participants]
     
Baseline: R5; Treatment failure: R5     9     14     10  
Baseline: R5; Treatment failure: X4     0     1     0  
Baseline: R5; Treatment failure: DM     4     11     0  
Baseline: R5; Treatment failure: NR/NP     6     7     5  
Baseline: DM; Treatment failure: R5     0     1     1  
Baseline: DM; Treatment failure: X4     0     2     0  
Baseline: DM; Treatment failure: DM     5     4     0  
Baseline: DM; Treatment failure: NR/NP     0     0     0  
Baseline: NR/NP; Treatment failure: R5     0     1     0  
Baseline: NR/NP; Treatment failure: X4     0     0     0  
Baseline: NR/NP; Treatment failure: DM     0     0     0  
Baseline: NR/NP; Treatment failure: NR/NP     0     1     0  

No statistical analysis provided for Number of Participants Per Tropism Status at Baseline and at the Time of Treatment Failure Through Week 96



12.  Secondary:   Number of Participants With Phenotypic Resistance at Time of Treatment Failure Through Week 48 and 96   [ Time Frame: Screening, time of failure through Week 48, Week 96 ]

Measure Type Secondary
Measure Title Number of Participants With Phenotypic Resistance at Time of Treatment Failure Through Week 48 and 96
Measure Description Phenotypic resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) assessed at screening by Monogram Bioscience PhenoSense genotype (MBPSGT) assay, repeated if viral load >500 copies/mL at treatment failure through week 48, 96. Phenotypic resistance to maraviroc was assumed in maraviroc treatment failures with X4-using virus and in R5 maraviroc treatment failures using Monogram Bioscience PhenoSense Entry Assay. Phenotypic resistance to zidovudine, lamivudine, efavirenz and maraviroc at time of failure was summarized.
Time Frame Screening, time of failure through Week 48, Week 96  
Safety Issue No  

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 population included all the randomized participants who had taken at least 1 dose of the study medication. ‘n’ is signifying those participants who experienced treatment failure, defined as discontinuation due to insufficient response at specified time points for each arm group respectively.

Reporting Groups
  Description
Maraviroc Once Daily + CBV (DB), Then Twice Daily + CBV (OL) Maraviroc 300 milligram (mg) tablet orally once daily in the evening along with placebo matched to maraviroc 300 mg tablet orally once daily in the morning and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase prior to the termination of the treatment arm based on the recommendation of the DSMB following a planned interim analysis. Eligible participants then switched to open-label maraviroc 300 mg tablet orally twice daily co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily for the remainder of the study.
Maraviroc Twice Daily + CBV (DB) Maraviroc 300 mg tablet orally twice daily and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.
Efavirenz Once Daily + CBV (DB) Placebo matched to maraviroc 300 mg tablet orally twice daily and efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.

Measured Values
    Maraviroc Once Daily + CBV (DB), Then Twice Daily + CBV (OL)     Maraviroc Twice Daily + CBV (DB)     Efavirenz Once Daily + CBV (DB)  
Number of Participants Analyzed  
[units: participants]
  174     360     361  
Number of Participants With Phenotypic Resistance at Time of Treatment Failure Through Week 48 and 96  
[units: participants]
     
Resistance to Zidovudine: Week 48 (n= 20, 43, 15)     0     0     0  
Resistance to Lamivudine: Week 48 (n= 20, 43, 15)     14     27     3  
Resistance to Efavirenz: Week 48 (n= 20, 43, 15)     0     0     7  
Resistance to Maraviroc: Week 48 (n= 20, 43, 15)     NA [1]   12     NA [2]
Resistance to Zidovudine: Week 96 (n= 27, 55, 23)     0     0     0  
Resistance to Lamivudine: Week 96 (n= 27, 55, 23)     20     33     8  
Resistance to Efavirenz: Week 96 (n= 27, 55, 23)     0     0     13  
Resistance to Maraviroc: Week 96 (n= 27, 55, 23)     NA [1]   NA [3]   NA [2]
[1] Data not summarized since treatment arm was stopped at Week 16 as it failed to meet pre-specified criteria.
[2] Data not summarized as maraviroc resistance was not relevant to efavirenz activity.
[3] Data not summarized since Week 96 analysis included participants who experienced TLOVR defined virologic failure in addition to those with treatment failure.

No statistical analysis provided for Number of Participants With Phenotypic Resistance at Time of Treatment Failure Through Week 48 and 96



13.  Secondary:   Number of Participants With NRTI Associated Mutations at Time of Treatment Failure Through Week 48 and 96   [ Time Frame: Screening, time of failure through Week 48, Week 96 ]

Measure Type Secondary
Measure Title Number of Participants With NRTI Associated Mutations at Time of Treatment Failure Through Week 48 and 96
Measure Description Genotypic resistance to NRTIs was assessed by identification of relevant mutations at screening using MBPSGT assay and repeated for all participants with HIV-1 viral load more than 500 copies/mL at treatment failure through week 48 and week 96. Following mutations associated with NRTIs were summarized at time of failure: Any zidovudine/lamivudine (Zid/Lam), Any thymidine analogue-associated mutation (TAM), methionine (M) to valine/isoleucine (V/I) substitution at residue (r) 184 (M184V/I), lysine (K) to arginine (R) substitution at residue 65 (K65R) and any other NRTI mutations.
Time Frame Screening, time of failure through Week 48, Week 96  
Safety Issue No  

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 population included all the randomized participants who had taken at least 1 dose of the study medication. ‘n’ is signifying those participants who experienced treatment failure, defined as discontinuation due to insufficient response at specified time points for each arm group respectively.

Reporting Groups
  Description
Maraviroc Once Daily + CBV (DB), Then Twice Daily + CBV (OL) Maraviroc 300 milligram (mg) tablet orally once daily in the evening along with placebo matched to maraviroc 300 mg tablet orally once daily in the morning and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase prior to the termination of the treatment arm based on the recommendation of the DSMB following a planned interim analysis. Eligible participants then switched to open-label maraviroc 300 mg tablet orally twice daily co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily for the remainder of the study.
Maraviroc Twice Daily + CBV (DB) Maraviroc 300 mg tablet orally twice daily and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.
Efavirenz Once Daily + CBV (DB) Placebo matched to maraviroc 300 mg tablet orally twice daily and efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.

Measured Values
    Maraviroc Once Daily + CBV (DB), Then Twice Daily + CBV (OL)     Maraviroc Twice Daily + CBV (DB)     Efavirenz Once Daily + CBV (DB)  
Number of Participants Analyzed  
[units: participants]
  174     360     361  
Number of Participants With NRTI Associated Mutations at Time of Treatment Failure Through Week 48 and 96  
[units: participants]
     
Any Zid/Lam Mutation: Week 48 (n= 20, 43, 15)     14     27     3  
Any TAM Mutation: Week 48 (n= 20, 43, 15)     1     6     0  
K65R Mutation: Week 48 (n= 20, 43, 15)     0     1     0  
M184V/I Mutation: Week 48 (n= 20, 43, 15)     14     27     3  
Other NRTI Mutation: Week 48 (n= 20, 43, 15)     0     1     0  
Any Zid/Lam Mutation: Week 96 (n= 27, 55, 23)     20     33     8  
Any TAM Mutation: Week 96 (n= 27, 55, 23)     3     6     2  
K65R Mutation: Week 96 (n= 27, 55, 23)     0     1     0  
M184V/I Mutation: Week 96 (n= 27, 55, 23)     20     33     8  
Other NRTI Mutation: Week 96 (n= 27, 55, 23)     0     1     0  

No statistical analysis provided for Number of Participants With NRTI Associated Mutations at Time of Treatment Failure Through Week 48 and 96



14.  Secondary:   Number of Participants With Efavirenz Associated Mutations at Time of Treatment Failure Through Week 48 and 96   [ Time Frame: Screening, time of failure through Week 48, Week 96 ]

Measure Type Secondary
Measure Title Number of Participants With Efavirenz Associated Mutations at Time of Treatment Failure Through Week 48 and 96
Measure Description Genotypic resistance: mutations at screening by MBPSGT assay, repeated if viral load >500 copies/mL at treatment failure through week 48, 96. Efavirenz mutation:lysine to aspargine at r103(K103N);tyrosine to cysteine/isoleucine at r181(Y181C/I);tyrosine to cysteine/leucine/histidine at r188(Y188C/L/H);glycine to alanine/serine at r190(G190A/S);valine to alanine to r106(V106A);leucine to isoleucine at r100(L100I);alanine to glycine at r98(A98G);lysine to glutamic acid at r101(K101E);valine to isoleucine at r108(V108I);proline to histidine at r225(P225H);methionine to leucine at r230(M230L).
Time Frame Screening, time of failure through Week 48, Week 96  
Safety Issue No  

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 population; n=participants with treatment failure at specified time points for each arm group respectively. Data not analyzed for participants originally randomized to maraviroc once daily arm since after termination focus shifted from efficacy, safety to only safety as reflected in abbreviated set of efficacy noted in amended planned analysis.

Reporting Groups
  Description
Maraviroc Twice Daily + CBV (DB) Maraviroc 300 mg tablet orally twice daily and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.
Efavirenz Once Daily + CBV (DB) Placebo matched to maraviroc 300 mg tablet orally twice daily and efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.

Measured Values
    Maraviroc Twice Daily + CBV (DB)     Efavirenz Once Daily + CBV (DB)  
Number of Participants Analyzed  
[units: participants]
  360     361  
Number of Participants With Efavirenz Associated Mutations at Time of Treatment Failure Through Week 48 and 96  
[units: participants]
   
L100I Mutation: Week 48 (n= 43, 15)     0     0  
K103N Mutation: Week 48 (n= 43, 15)     0     6  
V106M Mutation: Week 48 (n= 43, 15)     0     0  
V108I Mutation: Week 48 (n= 43, 15)     1     0  
Y181C/I Mutation: Week 48 (n= 43, 15)     0     0  
Y188L Mutation: Week 48 (n= 43, 15)     0     0  
G190S/A Mutation: Week 48 (n= 43, 15)     0     1  
P225H Mutation: Week 48 (n= 43, 15)     0     0  
L100I Mutation: Week 96 (n= 55, 23)     0     0  
K103N Mutation: Week 96 (n= 55, 23)     0     12  
V106M Mutation: Week 96 (n= 55, 23)     0     1  
V108I Mutation: Week 96 (n= 55, 23)     1     1  
Y181C/I Mutation: Week 96 (n= 55, 23)     0     0  
Y188L Mutation: Week 96 (n= 55, 23)     0     0  
G190S/A Mutation: Week 96 (n= 55, 23)     0     2  
P225H Mutation: Week 96 (n= 55, 23)     0     1  

No statistical analysis provided for Number of Participants With Efavirenz Associated Mutations at Time of Treatment Failure Through Week 48 and 96



15.  Secondary:   Percentage of Participants With HIV-1 RNA Levels Less Than 50 Copies/mL at Week 48 and Week 96 by Overall Susceptibility Score (OSS) at Screening   [ Time Frame: Baseline, Week 48, Week 96 ]

Measure Type Secondary
Measure Title Percentage of Participants With HIV-1 RNA Levels Less Than 50 Copies/mL at Week 48 and Week 96 by Overall Susceptibility Score (OSS) at Screening
Measure Description Association between baseline resistance and virological response was assessed as percentage of participants with HIV-1RNA levels less than 50 copies/mL by OSS at screening. OSS categorized as 0, 1, 2, >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= resistant, 1= sensitive or susceptible) for each antiretroviral agent in OBT. Higher scores indicate greater susceptibility.
Time Frame Baseline, Week 48, Week 96  
Safety Issue No  

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.
Data not analyzed because of insufficient diversity amongst participants with respect to baseline resistance due to the study entry criteria regarding baseline resistance.

Reporting Groups
  Description
Maraviroc Once Daily + CBV (DB), Then Twice Daily + CBV (OL) Maraviroc 300 milligram (mg) tablet orally once daily in the evening along with placebo matched to maraviroc 300 mg tablet orally once daily in the morning and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase prior to the termination of the treatment arm based on the recommendation of the DSMB following a planned interim analysis. Eligible participants then switched to open-label maraviroc 300 mg tablet orally twice daily co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily for the remainder of the study.
Maraviroc Twice Daily + CBV (DB) Maraviroc 300 mg tablet orally twice daily and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.
Efavirenz Once Daily + CBV (DB) Placebo matched to maraviroc 300 mg tablet orally twice daily and efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.

Measured Values
    Maraviroc Once Daily + CBV (DB), Then Twice Daily + CBV (OL)     Maraviroc Twice Daily + CBV (DB)     Efavirenz Once Daily + CBV (DB)  
Number of Participants Analyzed  
[units: participants]
  0     0     0  
Percentage of Participants With HIV-1 RNA Levels Less Than 50 Copies/mL at Week 48 and Week 96 by Overall Susceptibility Score (OSS) at Screening              

No statistical analysis provided for Percentage of Participants With HIV-1 RNA Levels Less Than 50 Copies/mL at Week 48 and Week 96 by Overall Susceptibility Score (OSS) at Screening



16.  Other Pre-specified:   Percentage of Participants With Viral Load of Less Than 400 Copies/mL and Less Than 50 Copies/mL of HIV-1 RNA at Week 96   [ Time Frame: Week 96 ]

Measure Type Other Pre-specified
Measure Title Percentage of Participants With Viral Load of Less Than 400 Copies/mL and Less Than 50 Copies/mL of HIV-1 RNA at Week 96
Measure Description No text entered.
Time Frame Week 96  
Safety Issue No  

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 population included all the randomized participants who had taken at least 1 dose of the study medication. Missing data (MD) imputed as failure (F); that is, participants with missing data classified as not achieving the viral load criterion (MD=F).

Reporting Groups
  Description
Maraviroc Once Daily + CBV (DB), Then Twice Daily + CBV (OL) Maraviroc 300 milligram (mg) tablet orally once daily in the evening along with placebo matched to maraviroc 300 mg tablet orally once daily in the morning and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase prior to the termination of the treatment arm based on the recommendation of the DSMB following a planned interim analysis. Eligible participants then switched to open-label maraviroc 300 mg tablet orally twice daily co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily for the remainder of the study.
Maraviroc Twice Daily + CBV (DB) Maraviroc 300 mg tablet orally twice daily and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.
Efavirenz Once Daily + CBV (DB) Placebo matched to maraviroc 300 mg tablet orally twice daily and efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.

Measured Values
    Maraviroc Once Daily + CBV (DB), Then Twice Daily + CBV (OL)     Maraviroc Twice Daily + CBV (DB)     Efavirenz Once Daily + CBV (DB)  
Number of Participants Analyzed  
[units: participants]
  174     360     361  
Percentage of Participants With Viral Load of Less Than 400 Copies/mL and Less Than 50 Copies/mL of HIV-1 RNA at Week 96  
[units: Percentage of participants]
     
Less than 400 copies/mL     52.9     61.4     64.5  
Less than 50 copies/mL     48.3     56.9     62.6  


Statistical Analysis 1 for Percentage of Participants With Viral Load of Less Than 400 Copies/mL and Less Than 50 Copies/mL of HIV-1 RNA at Week 96
Groups [1] Maraviroc Twice Daily + CBV (DB) vs. Efavirenz Once Daily + CBV (DB)
Non-Inferiority/Equivalence Test [2] Yes
Difference in Percentage [3] -3.2
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Less than 400 copies/mL: Treatment difference in percentage stratified by randomization strata was presented along with the lower bound of the 1-sided 97.5% CI based on the normal approximation to the binomial distribution. Positive value would favor maraviroc. Step down procedure used to control for multiple comparisons.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Non-inferiority was to be concluded if the lower bound of the 1-sided 97.5% CI was greater than (>) -10%.
[3] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Percentage of Participants With Viral Load of Less Than 400 Copies/mL and Less Than 50 Copies/mL of HIV-1 RNA at Week 96
Groups [1] Maraviroc Twice Daily + CBV (DB) vs. Efavirenz Once Daily + CBV (DB)
Non-Inferiority/Equivalence Test [2] Yes
Difference in Percentage [3] -5.8
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Less than 50 copies/mL: Treatment difference in percentage stratified by randomization strata was presented along with the lower bound of the 1-sided 97.5% CI based on the normal approximation to the binomial distribution. Positive value would favor maraviroc. Step down procedure used to control for multiple comparisons.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Non-inferiority was to be concluded if the lower bound of the 1-sided 97.5% CI was > -10%.
[3] Other relevant estimation information:
  No text entered.



17.  Post-Hoc:   Percentage of Participants With HIV-1 RNA Levels of Less Than 400 Copies/mL and Less Than 50 Copies/mL at Week 48 for Enhanced Sensitivity Trofile Assay (ESTA) R5 Participants   [ Time Frame: Week 48 ]

Measure Type Post-Hoc
Measure Title Percentage of Participants With HIV-1 RNA Levels of Less Than 400 Copies/mL and Less Than 50 Copies/mL at Week 48 for Enhanced Sensitivity Trofile Assay (ESTA) R5 Participants
Measure Description Percentage of participants with HIV-1 RNA levels of less than 400 copies/mL and less than 50 copies/mL were not analyzed for maraviroc once daily, then twice daily arm in order to avoid misinterpretation due to possible bias due to the fact that only a non-random sample of participants in the terminated arm were re-assayed with ESTA.
Time Frame Week 48  
Safety Issue No  

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 population; 'N' number of participants analyzed included ESTA R5 participants who had R5 tropic virus by ESTA at screening. Missing data (MD) imputed as failure (F); that is, participants with missing data classified as not achieving the viral load criterion (MD=F).

Reporting Groups
  Description
Maraviroc Twice Daily + CBV (DB) Maraviroc 300 mg tablet orally twice daily and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.
Efavirenz Once Daily + CBV (DB) Placebo matched to maraviroc 300 mg tablet orally twice daily and efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.

Measured Values
    Maraviroc Twice Daily + CBV (DB)     Efavirenz Once Daily + CBV (DB)  
Number of Participants Analyzed  
[units: participants]
  311     303  
Percentage of Participants With HIV-1 RNA Levels of Less Than 400 Copies/mL and Less Than 50 Copies/mL at Week 48 for Enhanced Sensitivity Trofile Assay (ESTA) R5 Participants  
[units: Percentage of participants]
   
Less than 400 copies/mL     73.3     72.3  
Less than 50 copies/mL     68.5     68.3  


Statistical Analysis 1 for Percentage of Participants With HIV-1 RNA Levels of Less Than 400 Copies/mL and Less Than 50 Copies/mL at Week 48 for Enhanced Sensitivity Trofile Assay (ESTA) R5 Participants
Groups [1] All groups
Difference in Percentage [2] 0.6
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Less than 400 copies/mL: Treatment difference in percentage stratified by randomization strata was presented along with the lower bound of the 1-sided 97.5% CI based on the normal approximation to the binomial distribution. Positive value would favor maraviroc. Due to its post-hoc nature, this analysis was considered descriptive only rather than inferential.
[2] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Percentage of Participants With HIV-1 RNA Levels of Less Than 400 Copies/mL and Less Than 50 Copies/mL at Week 48 for Enhanced Sensitivity Trofile Assay (ESTA) R5 Participants
Groups [1] All groups
Difference in Percentage [2] -0.2
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Less than 50 copies/mL: Treatment difference in percentage stratified by randomization strata was presented along with the lower bound of the 1-sided 97.5% CI based on the normal approximation to the binomial distribution. Positive value would favor maraviroc. Due to its post-hoc nature, this analysis was considered descriptive only rather than inferential.
[2] Other relevant estimation information:
  No text entered.



18.  Post-Hoc:   Percentage of Participants With HIV-1 RNA Levels of Less Than 400 Copies/mL and Less Than 50 Copies/mL at Week 96 for Enhanced Sensitivity Trofile Assay (ESTA) R5 Participants   [ Time Frame: Week 96 ]

Measure Type Post-Hoc
Measure Title Percentage of Participants With HIV-1 RNA Levels of Less Than 400 Copies/mL and Less Than 50 Copies/mL at Week 96 for Enhanced Sensitivity Trofile Assay (ESTA) R5 Participants
Measure Description Percentage of participants with HIV-1 RNA levels of less than 400 copies/mL and less than 50 copies/mL were not analyzed for maraviroc once daily, then twice daily arm in order to avoid misinterpretation due to possible bias due to the fact that only a non-random sample of participants in the terminated arm were re-assayed with ESTA.
Time Frame Week 96  
Safety Issue No  

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 population; 'N' number of participants analyzed included ESTA R5 participants who had R5 tropic virus by ESTA at screening. Missing data (MD) imputed as failure (F); that is, participants with missing data classified as not achieving the viral load criterion (MD=F).

Reporting Groups
  Description
Maraviroc Twice Daily + CBV (DB) Maraviroc 300 mg tablet orally twice daily and placebo matched to efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.
Efavirenz Once Daily + CBV (DB) Placebo matched to maraviroc 300 mg tablet orally twice daily and efavirenz 600 mg tablet orally once daily in the evening co-administered with combination therapy containing zidovudine 300 mg and lamivudine 150 mg (combivir [CBV]) tablet orally twice daily, during the DB phase.

Measured Values
    Maraviroc Twice Daily + CBV (DB)     Efavirenz Once Daily + CBV (DB)  
Number of Participants Analyzed  
[units: participants]
  311     303  
Percentage of Participants With HIV-1 RNA Levels of Less Than 400 Copies/mL and Less Than 50 Copies/mL at Week 96 for Enhanced Sensitivity Trofile Assay (ESTA) R5 Participants  
[units: Percentage of participants]
   
Less than 400 copies/mL     64.0     64.4  
Less than 50 copies/mL     58.8     62.7  


Statistical Analysis 1 for Percentage of Participants With HIV-1 RNA Levels of Less Than 400 Copies/mL and Less Than 50 Copies/mL at Week 96 for Enhanced Sensitivity Trofile Assay (ESTA) R5 Participants
Groups [1] All groups
Difference in Percentage [2] -0.4
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Less than 400 copies/mL: Treatment difference in percentage stratified by randomization strata was presented along with the lower bound of the 1-sided 97.5% CI based on the normal approximation to the binomial distribution. Positive value would favor maraviroc. Due to its post-hoc nature, this analysis was considered descriptive only rather than inferential.
[2] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Percentage of Participants With HIV-1 RNA Levels of Less Than 400 Copies/mL and Less Than 50 Copies/mL at Week 96 for Enhanced Sensitivity Trofile Assay (ESTA) R5 Participants
Groups [1] All groups
Difference in Percentage [2] -3.9
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Less than 50 copies/mL: Treatment difference in percentage stratified by randomization strata was presented along with the lower bound of the 1-sided 97.5% CI based on the normal approximation to the binomial distribution. Positive value would favor maraviroc. Due to its post-hoc nature, this analysis was considered descriptive only rather than inferential.
[2] Other relevant estimation information:
  No text entered.




  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
Following DSMB decision to discontinue maraviroc 300 mg once daily, inferential statistical analyses was performed between maraviroc 300 mg twice daily and efavirenz 600 mg once daily only. Data at Week 24 was not analyzed as planned in protocol.


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