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

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

  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
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Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups
  Description
Maraviroc QD Maraviroc 150 mg by mouth (PO) once daily (QD) in combination with optimized background therapy (OBT) (3 to 6 drugs based on treatment history and resistance testing). The 150 mg QD arm = placebo drug in the morning and active drug in the evening.
Maraviroc BID Maraviroc 150 mg PO twice a day (BID) in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The 150 mg BID arm = active drug in the morning and evening.
Placebo Placebo BID in combination with OBT (3 to 6 drugs based on treatment history and resistance testing). The placebo arm = placebo drug in the morning and evening.

Participant Flow for 3 periods

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

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

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



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

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



  Outcome Measures
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1.  Primary:   Change From Baseline in Human Immunodeficiency Virus (HIV-1) Viral Load (Ribonucleic Acid [RNA])   [ Time Frame: Baseline to Week 24 and Week 48 ]
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Measure Type Primary
Measure Title Change From Baseline in Human Immunodeficiency Virus (HIV-1) Viral Load (Ribonucleic Acid [RNA])
Measure Description Change from baseline in log 10-transformed plasma viral load (HIV-1 RNA) levels (log 10 copies per milliliter [log10 copies/mL]). Baseline value calculated as average of pre-dose measurements collected at screening, randomization, and baseline visits.
Time Frame Baseline to Week 24 and Week 48  
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.
Full Analysis Set (FAS)-as treated: all randomized subjects classified as dual-tropic by phenotype assay; received at least 1 dose of study treatment. Missing values: discontinuations (DC) imputed as baseline value (change from baseline=0); missing data imputed as Last Observation Carried Forward (LOCF).

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

Measured Values
    Maraviroc QD     Maraviroc BID     Placebo  
Number of Participants Analyzed  
[units: participants]
  57     52     58  
Change From Baseline in Human Immunodeficiency Virus (HIV-1) Viral Load (Ribonucleic Acid [RNA])  
[units: log10┬ácopies/mL]
Mean ± Standard Error
     
Week 24     -0.890  ± 0.1706     -1.194  ± 0.2060     -0.953  ± 0.1795  
Week 48     -0.604  ± 0.1596     -1.105  ± 0.2071     0.839  ± 0.1851  


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

Statistical Analysis 2 for Change From Baseline in Human Immunodeficiency Virus (HIV-1) Viral Load (Ribonucleic Acid [RNA])
Groups [1] Maraviroc BID vs. Placebo
Method [2] ANCOVA
Least squares mean [3] -0.232
Standard Error of the mean ± 0.2637
97.5% Confidence Interval ( -0.829 to 0.364 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC BID vs PBO treatment difference at Week 24.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  TX difference adjusted for randomization strata. Bonferroni adjustment for multiple comparisons by use of 2-sided 97.5% CI to maintain alpha=0.05.
[3] Other relevant estimation information:
  Negative values for change from baseline=benefit of TX; negative values for MVC vs PBO=advantage of MVC.

Statistical Analysis 3 for Change From Baseline in Human Immunodeficiency Virus (HIV-1) Viral Load (Ribonucleic Acid [RNA])
Groups [1] Maraviroc QD vs. Placebo
Method [2] ANCOVA
Least squares mean [3] 0.229
Standard Error of the mean ± 0.2567
97.5% Confidence Interval ( -0.351 to 0.810 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC QD vs PBO treatment difference at Week 48.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  TX difference adjusted for randomization strata. Bonferroni adjustment for multiple comparisons by use of 2-sided 97.5% CI to maintain alpha=0.05.
[3] Other relevant estimation information:
  Negative values for change from baseline=benefit of TX; negative values for MVC vs PBO=advantage of MVC.

Statistical Analysis 4 for Change From Baseline in Human Immunodeficiency Virus (HIV-1) Viral Load (Ribonucleic Acid [RNA])
Groups [1] Maraviroc BID vs. Placebo
Method [2] ANCOVA
Least squares mean [3] -0.261
Standard Error of the mean ± 0.2628
97.5% Confidence Interval ( -0.856 to 0.333 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MVC BID vs PBO treatment difference at Week 48.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  TX difference adjusted for randomization strata. Bonferroni adjustment for multiple comparisons by use of 2-sided 97.5% CI to maintain alpha=0.05.
[3] Other relevant estimation information:
  Negative values for change from baseline=benefit of TX; negative values for MVC vs PBO=advantage of MVC.



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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


  Serious Adverse Events


  Other Adverse Events


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