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: January 10, 2013

Last verified: January 2013

History of Changes

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
Double-blind phase nominally ended at last participant’s week 96 visit,open-label (OL) phase continued for at least 3 years after this. 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 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.
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. 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 OL 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. 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.
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.

Participant Flow for 3 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)
STARTED	177	368	372
Treated	174	360	361
COMPLETED	0	202	202
NOT COMPLETED	177	166	170
Adverse Event	14	27	60
Pregnancy	0	7	9
Participant Defaulted	11	40	36
Lack of Efficacy	11	64	30
Death	1	2	2
Randomized, Not Treated	3	8	11
Protocol Violation	2	18	22
Terminated by sponsor	135	0	0

Period 2: Between DB and OL Phase

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

Period 3: Open-label (OL) Phase

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

Baseline Characteristics

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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.
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. 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 OL 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 ]

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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 ]

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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 ]

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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 ]

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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 ]

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6. Secondary:

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

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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 ]

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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 ]

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9. Secondary:

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

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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 ]

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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 ]

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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 ]

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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 ]

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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 ]

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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 ]

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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 ]

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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 ]

Show Outcome Measure 17

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 ]

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Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.

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.

Results Point of Contact:

Name/Title: Pfizer ClinicalTrials.gov Call Center
Organization: Pfizer, Inc.
phone: 1-800-718-1021
e-mail: ClinicalTrials.gov_Inquiries@pfizer.com

No publications provided by ViiV Healthcare

Publications automatically indexed to this study:

MacInnes A, Lazzarin A, Di Perri G, Sierra-Madero JG, Aberg J, Heera J, Rajicic N, Goodrich J, Mayer H, Valdez H. Maraviroc can improve lipid profiles in dyslipidemic patients with HIV: results from the MERIT trial. HIV Clin Trials. 2011 Jan-Feb;12(1):24-36.

Funderburg N, Kalinowska M, Eason J, Goodrich J, Heera J, Mayer H, Rajicic N, Valdez H, Lederman MM. Effects of maraviroc and efavirenz on markers of immune activation and inflammation and associations with CD4+ cell rises in HIV-infected patients. PLoS One. 2010 Oct 6;5(10):e13188.

Cooper DA, Heera J, Goodrich J, Tawadrous M, Saag M, Dejesus E, Clumeck N, Walmsley S, Ting N, Coakley E, Reeves JD, Reyes-Teran G, Westby M, Van Der Ryst E, Ive P, Mohapi L, Mingrone H, Horban A, Hackman F, Sullivan J, Mayer H. Maraviroc versus Efavirenz, both in combination with zidovudine-lamivudine, for the treatment of antiretroviral-naive subjects with CCR5-tropic HIV-1 infection. J Infect Dis. 2010 Mar 15;201(6):803-13.

Responsible Party:	ViiV Healthcare
ClinicalTrials.gov Identifier:	NCT00098293 History of Changes
Other Study ID Numbers:	A4001026
Study First Received:	December 6, 2004
Results First Received:	July 9, 2012
Last Updated:	January 10, 2013
Health Authority:	United States: Food and Drug Administration

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