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 ]

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 ]

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 ]

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 ]

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 ]

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

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 ]

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 ]

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

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 ]

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 ]

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 ]

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 ]

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 ]

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 ]

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 ]

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 ]

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 ]


  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
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.


  More Information