Trial record 3 of 3 for: A5257

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Comparative Study of Three NNRTI-Sparing HAART Regimens

This study has been completed.

Sponsor:

Collaborators:

National Institute of Allergy and Infectious Diseases (NIAID)

Bristol-Myers Squibb

Gilead Sciences

Merck Sharp & Dohme Corp.

Tibotec Therapeutics, a Division of Ortho Biotech Products, L.P., USA

Information provided by (Responsible Party):

AIDS Clinical Trials Group

ClinicalTrials.gov Identifier:

NCT00811954

First received: December 18, 2008

Last updated: September 4, 2014

Last verified: September 2014

History of Changes

Results First Received: June 23, 2014

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Open Label; Primary Purpose: Treatment
Condition:	HIV Infection
Interventions:	Drug: Emtricitabine/tenofovir disoproxil fumarate Drug: Raltegravir Drug: Darunavir Drug: Ritonavir Drug: Atazanavir

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
Recruited at AIDS Clinical Trials Units in the United States and Puerto Rico. Recruitment occurred between May 22, 2009 (date first subject was randomized) and June 9, 2011 (date last subject was randomized).

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
1814 were randomized 1:1:1 to treatment arms A, B, and C. Results reported for 1809 eligible participants; 5 were subsequently found ineligible and excluded from all analyses.

Reporting Groups

Description

Arm A: ATV/RTV + FTC/TDF

Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), ritonavir (RTV), and atazanavir (ATV) to be taken orally, once daily.

Emtricitabine/tenofovir disoproxil fumarate: A combination drug of two nucleoside reverse transcriptase inhibitors (NRTIs) Ritonavir: A protease inhibitor (PI) Atazanavir: A protease inhibitor (PI)

Arm B: RAL + FTC/TDF

FTC/TDF orally, once daily, and raltegravir (RAL) orally, twice daily.

Emtricitabine/tenofovir disoproxil fumarate: A combination drug of two nucleoside reverse transcriptase inhibitors (NRTIs) Raltegravir: An integrase inhibitor (INI)

Arm C: DRV/RTV + FTC/TDF

FTC/TDF, darunavir (DRV), and RTV, orally, once daily.

Emtricitabine/tenofovir disoproxil fumarate: A combination drug of two nucleoside reverse transcriptase inhibitors (NRTIs) Darunavir: A protease inhibitor (PI) Ritonavir: A protease inhibitor (PI)

Participant Flow: Overall Study

	Arm A: ATV/RTV + FTC/TDF	Arm B: RAL + FTC/TDF	Arm C: DRV/RTV + FTC/TDF
STARTED	605	603	601
COMPLETED	516	531	500
NOT COMPLETED	89	72	101
Death	10	6	13
Lost to Follow-up	29	23	34
Not able to get to clinic	28	35	30
Not willing to adhere to requirements	12	2	16
Withdraw consent prior study completion	4	6	5
Site Closure	4	0	1
Severe Debilitation	2	0	1
Complete Protocol: No follow-up	0	0	1

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.
Intention to treat: All eligible participants were included in the baseline characteristics.

Reporting Groups

	Description
Arm A: ATV/RTV + FTC/TDF	Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), ritonavir (RTV), and atazanavir (ATV) to be taken orally, once daily. Emtricitabine/tenofovir disoproxil fumarate: A combination drug of two nucleoside reverse transcriptase inhibitors (NRTIs) Ritonavir: A protease inhibitor (PI) Atazanavir: A protease inhibitor (PI)
Arm B: RAL + FTC/TDF	FTC/TDF orally, once daily, and raltegravir (RAL) orally, twice daily. Emtricitabine/tenofovir disoproxil fumarate: A combination drug of two nucleoside reverse transcriptase inhibitors (NRTIs) Raltegravir: An integrase inhibitor (INI)
Arm C: DRV/RTV + FTC/TDF	FTC/TDF, darunavir (DRV), and RTV, orally, once daily. Emtricitabine/tenofovir disoproxil fumarate: A combination drug of two nucleoside reverse transcriptase inhibitors (NRTIs) Darunavir: A protease inhibitor (PI) Ritonavir: A protease inhibitor (PI)
Total	Total of all reporting groups

Baseline Measures

	Arm A: ATV/RTV + FTC/TDF	Arm B: RAL + FTC/TDF	Arm C: DRV/RTV + FTC/TDF	Total
Number of Participants [units: participants]	605	603	601	1809
Age [units: participants]
<=18 years	2	2	2	6
Between 18 and 65 years	597	598	595	1790
>=65 years	6	3	4	13
Age [units: years] Mean ± Standard Deviation	38 ± 11	37 ± 11	38 ± 11	37 ± 11
Gender [units: participants]
Female	144	148	143	435
Male	461	455	458	1374
Race/Ethnicity, Customized ^[1] [units: participants]
White Non-Hispanic	212	212	191	615
Black Non-Hispanic	252	254	251	757
Hispanic (Regardless of Race)	125	117	148	390
Asian, Pacific Islander	11	13	6	30
American Indian, Alaskan Native	2	2	2	6
More than one race	2	3	2	7
Unknown/missing	1	2	1	4
HIV-1 RNA ^[2] [units: log10 copies/mL] Mean ± Standard Deviation	4.6 ± 0.7	4.6 ± 0.7	4.6 ± 0.7	4.6 ± 0.7
CD4+ T-cell count ^[3] [units: cells/mm^3] Mean ± Standard Deviation	309 ± 189	306 ± 199	310 ± 189	308 ± 192

[1]	Race/Ethnicity was collected prior to study entry
[2]	HIV-1 RNA was calculated as the geometric mean of the two most recent HIV-1 RNA (log 10 copies/mL) obtained on or before study entry. In the event that these two values differed by more than 1log10 copy/mL, the outlying value (based on review of all HIV-1 RNA levels available prior to study entry by the study virologist) was excluded and baseline determined by the remaining sample. Note that screening HIV-1 RNA values were not sued in the calculation of baseline HIV-1 RNA levels.
[3]	CD4+ T-cell counts were calculated as the mean of the two most recent values available on or before study entry.

Outcome Measures

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1. Primary:

Cumulative Probability of First Virologic Failure by Week 96 [ Time Frame: From study entry to week 96 ]

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2. Primary:

Cumulative Incidence of Discontinuation of the RAL or PI Component of Randomized Treatment for Toxicity by Week 96 [ Time Frame: From study entry to week 96 ]

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3. Secondary:

Cumulative Incidence of First Adverse Event by Week 96 [ Time Frame: From study entry to week 96 ]

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4. Secondary:

Cumulative Probability of Time to Loss of Virologic Response (TLOVR) by Week 96 [ Time Frame: From study entry to week 96 ]

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5. Secondary:

Presence of Mutations Associated With NRTI Resistance [ Time Frame: At the virologic failure at any time throughout the study (up to 213 weeks) ]

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6. Secondary:

Presence of Mutations Associated With ATV/RTV or DRV/RTV Resistance [ Time Frame: At the virologic failure at any time throughout the study (up to 213 weeks) ]

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7. Secondary:

Presence of Mutations Associated With INI Resistance [ Time Frame: At the virologic failure at any time throughout the study (up to 213 weeks) ]

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8. Secondary:

CD4+ T-cell Count [ Time Frame: At Weeks 24, 48, 96, and 144 ]

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9. Secondary:

CD4+ T-cell Count Changes From Baseline [ Time Frame: Study entry to weeks 24, 48, 96, and 144 ]

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10. Secondary:

Incidence of Death or AIDS Defining Events (CDC Category C) [ Time Frame: Study entry to off-study at any time throughout the study (up to 213 weeks), participant follow-up time was variable ]

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11. Secondary:

Incidence of Targeted Serious Non-AIDS Defining Events (Renal Failure, Liver Disease, Serious Metabolic Disorder, and CVD) [ Time Frame: Study entry to off-study at any time throughout the study (up to 213 weeks), participant follow-up time was variable ]

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12. Secondary:

Change in Fasting Total Cholesterol Level From Baseline [ Time Frame: Study entry to weeks 48, 96, and 144 ]

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13. Secondary:

Change in Fasting HDL Cholesterol Level From Baseline [ Time Frame: Study entry to weeks 48, 96, and 144 ]

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14. Secondary:

Change in Fasting Triglycerides Level From Baseline [ Time Frame: Study entry to weeks 48, 96, and 144 ]

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15. Secondary:

Change in Fasting Plasma Glucose Level From Baseline [ Time Frame: Study entry to weeks 48, 96, and 144 ]

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16. Secondary:

Change in Framingham 10-year Risk of MI or Coronary Death From Baseline [ Time Frame: Study entry to weeks 48, 96, and 144 ]

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17. Secondary:

Change in Waist Circumference From Baseline [ Time Frame: Study entry to weeks 48, 96, and 144 ]

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18. Secondary:

Change in Waist:Height Ratio From Baseline [ Time Frame: Study entry to weeks 48, 96, and 144 ]

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19. Secondary:

Self-reported Adherence [ Time Frame: At Weeks 4, 24, 48, 96, and 144 ]

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Serious Adverse Events

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Other Adverse Events

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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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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: In accordance with the Clinical Trials Agreement between NIAID (DAIDS) and company collaborators, NIAID (DAIDS) provides companies with a copy of any abstract, press release, or manuscript prior to submission for publication with sufficient time for company review and comment. The publication/other disclosure can be delayed for up to 30 additional business days for manuscripts and five (5) business days for abstracts, to preserve U.S. or foreign patent or other intellectual property rights.

Results Point of Contact:

Name/Title: ACTG Clinicaltrials.gov Coordinator
Organization: ACTG Network Coordinating Center, Social & Scientific Systems, Inc.
phone: (301) 628-3313
e-mail: ACTGCT.Gov@s-3.com

Publications:

Bartlett JA, Chen SS, Quinn JB. Comparative efficacy of nucleoside/nucleotide reverse transcriptase inhibitors in combination with efavirenz: results of a systematic overview. HIV Clin Trials. 2007 Jul-Aug;8(4):221-6. Review.

Duvivier C, Ghosn J, Assoumou L, Soulié C, Peytavin G, Calvez V, Génin MA, Molina JM, Bouchaud O, Katlama C, Costagliola D; ANRS 121 study group. Initial therapy with nucleoside reverse transcriptase inhibitor-containing regimens is more effective than with regimens that spare them with no difference in short-term fat distribution: Hippocampe-ANRS 121 Trial. J Antimicrob Chemother. 2008 Oct;62(4):797-808. doi: 10.1093/jac/dkn278. Epub 2008 Jul 18.

Markowitz M, Nguyen BY, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C, Prada G, Morales-Ramirez JO, Crumpacker CS, Isaacs RD, Gilde LR, Wan H, Miller MD, Wenning LA, Teppler H; Protocol 004 Part II Study Team. Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr. 2007 Oct 1;46(2):125-33.

Molina JM, Andrade-Villanueva J, Echevarria J, Chetchotisakd P, Corral J, David N, Moyle G, Mancini M, Percival L, Yang R, Thiry A, McGrath D; CASTLE Study Team. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet. 2008 Aug 23;372(9639):646-55. doi: 10.1016/S0140-6736(08)61081-8.

Publications automatically indexed to this study:

Lennox JL, Landovitz RJ, Ribaudo HJ, Ofotokun I, Na LH, Godfrey C, Kuritzkes DR, Sagar M, Brown TT, Cohn SE, McComsey GA, Aweeka F, Fichtenbaum CJ, Presti RM, Koletar SL, Haas DW, Patterson KB, Benson CA, Baugh BP, Leavitt RY, Rooney JF, Seekins D, Currier JS; ACTG A5257 Team. Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern Med. 2014 Oct 7;161(7):461-71. doi: 10.7326/M14-1084. Erratum in: Ann Intern Med. 2014 Nov 4;161(9):680.

Responsible Party:	AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:	NCT00811954 History of Changes
Other Study ID Numbers:	ACTG A5257, 1U01AI068636
Study First Received:	December 18, 2008
Results First Received:	June 23, 2014
Last Updated:	September 4, 2014
Health Authority:	United States: Federal Government

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