Clinical trial NCT00112047: Tenofovir Disoproxil Fumarate/Emtricitabine/Efavirenz Versus Combivir/Efavirenz in Antiretroviral-Naive HIV-1 Infected Subjects
Official title: A Phase 3, Randomized, Multicenter Study of the Treatment of Antiretroviral-Naive HIV-1 Infected Subjects Comparing Tenofovir Disoproxil Fumarate and Emtricitabine in Combination With Efavirenz vs Combivir (Lamivudine/Zidovudine) and Efavirenz
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infections
Keywords: Human Immunodeficiency Virus
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2005-05-30
Enrollment: 517
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of Study GS-01-934 was to assess the efficacy and safety of two simplified antiretroviral treatment (ART) regimens in ART-naive, human immunodeficiency virus, type 1 (HIV-1) infected participants. The primary objective of the study was to assess noninferiority of emtricitabine (FTC) and tenofovir disoproxil fumarate (tenofovir DF; TDF) in combination with efavirenz (EFV) relative to Combivir (CBV) in combination with EFV in the treatment of HIV-1 infected ART-naive participants, determined by the achievement and maintenance of confirmed HIV-1 ribonucleic acid (RNA) \< 400 copies/mL (c/mL) through Week 48, as defined by the United States (US) Food and Drug Administration (FDA) time-to-loss-of-virologic-response (TLOVR) algorithm.

Detailed description: This study was originally planned as a 48-week, Phase 3, randomized, open-label, multicenter study comparing EFV+FTC+TDF (administered as the individual component drugs) versus CBV (lamivudine/zidovudine) + EFV to assess the efficacy and safety of both treatments in ART-Naive, HIV-1 infected participants. The regimen of CBV (administered twice daily) + EFV (administered once daily) served as the active control treatment and was compared with the regimen of EFV+FTC+TDF; each component drug in the EFV+FTC+TDF regimen was administered once daily.

Week 48 to Week 96:

The study was extended and continued to evaluate the efficacy and safety of the two regimens up to a total treatment duration of 96 weeks. The regimen of EFV+FTC+TDF continued to be dosed as the component drugs (EFV + FTC + TDF), once daily, without regard to meals. The regimen of CBV+EFV was dosed as 2 pills (CBV, twice daily in the morning without regard to meals) + EFV (once daily, without regard to meals).

Week 96 to Week 144:

A further study extension changed the 3-pill EFV+FTC+TDF regimen to a 2-pill regimen of EFV + Truvada (\[TVD\]: a fixed-dose combination pill containing FTC/TDF), once daily without regard to meals, and continued to evaluate the efficacy and safety of the two regimens for a further 48 weeks up to a total study treatment duration of 144 weeks. The regimen of CBV+EFV continued to be dosed as 2 pills (CBV, twice daily in the morning without regard to meals) + EFV (once daily, without regard to meals).

Week 144 to end of study (Week 240):

A final study extension provided all study participants from both treatment regimens the option to switch their respective treatments to the 1-pill regimen of for a further 96 weeks up to a total study duration of 240 weeks (5 years) to further assess the efficacy and safety of ART regimen simplification. At sites in France, the study was extended by a further 48 weeks (Year 6) or until ATR became commercially available (whichever happened first); once ATR became commercially available in France participants were not required to complete the full 288 weeks of the study.

Eligibility criteria: Inclusion Criteria: Participants must have met all inclusion criteria within 28 days prior to randomization unless specified otherwise including:

* Plasma HIV-1 RNA levels greater than 10,000 c/mL using Roche Amplicor HIV-1 Monitor Test Version 1.5 Standard
* Adequate renal function: Calculated creatinine clearance greater than or equal to 50 mL/min according to the Cockcroft-Gault Formula.
* Hepatic transaminases (aspartate aminotransferase \[AST\] and alanine aminotransferase \[ALT\]) 3 x upper limit of normal (ULN).
* Total bilirubin less than or equal to 1.5 mg/dL.
* Adequate hematologic function (absolute neutrophil count greater than or equal to 1,000/mm\^3; platelets greater than or equal to 50,000/mm\^3; hemoglobin greater than or equal to 8.0 g/dL).
* Serum amylase less than or equal to 1.5 x ULN.
* Serum phosphorus greater than or equal to 2.2 mg/dL.
* Willingness to use effective contraception by both males and females while on study treatment and for 30 days following study drug completion.
* Life expectancy greater than or equal to 1 year
* The ability to understand and sign written informed consent form obtained prior to initiation of study procedures.

Exclusion Criteria: Participants were not eligible for entry to the study if any of the following were met:

* Prior treatment with any non-nucleoside reverse transcriptase inhibitor (NNRTI), nucleoside reverse transcriptase inhibitor (NRTI), or protease inhibitor (PI).
* A new AIDS-defining condition diagnosed (exception CD4 criteria) within 30 days of baseline.
* Receiving ongoing therapy with any of the following: nephrotoxic agents, probenecid, systemic chemotherapeutic agents, systemic corticosteroids, interleukin-2, drugs that interact with efavirenz. Administration of any of the above medications must be discontinued at least 30 days prior to baseline visit and for duration of study.
* Pregnant or lactating participants.
* Malignancy other than cutaneous Kaposi's sarcoma (KS) or basal cell carcinoma. Participants with biopsy-confirmed KS were eligible but must not have received any systemic therapy for KS within 30 days of baseline and not anticipated starting systemic therapy during the study.
* Prior history of renal or bone disease.
* Any other clinical condition prior to therapy that would make the participant unsuitable for the study or unable to comply with the dosing requirements in the opinion of the investigator.

Primary outcomes:
measure: Percentage of Participants With Confirmed Plasma HIV-1 RNA < 400 c/mL at Week 48 (Defined by the Food and Drug Administration [FDA] Time-to-Loss-of Virologic Response [TLOVR] Algorithm
timeFrame: 48 weeks
Secondary outcomes:
measure: Percentage of Participants With Confirmed Plasma HIV-1 RNA < 50 c/mL at Week 48 (Defined by FDA TLOVR Algorithm)
timeFrame: Week 48
measure: Percentage of Participants With Plasma HIV-1 RNA < 400 c/mL at Week 48.
timeFrame: 48 weeks
measure: Percentage of Participants With HIV-1 RNA < 50 c/mL at Week 48
timeFrame: 48 Weeks
measure: Percentage of Participants With Loss of Virologic Response (HIV-1 RNA < 400 c/mL) at Week 48
timeFrame: Baseline to 48 weeks
measure: Percentage of Participants With Loss of Virologic Response (HIV-1 RNA < 50 c/mL) at Week 48
timeFrame: Baseline to 48 Weeks
measure: Percentage of Participants With Pure Virologic Failure (HIV-1 RNA < 400 c/mL) at Week 48
timeFrame: Baseline to 48 Weeks
measure: Percentage of Participants With Pure Virologic Failure (HIV-1 RNA < 50 c/mL) at Week 48
timeFrame: Baseline to 48 Weeks
measure: Change From Study Baseline in HIV-1 RNA (Log10 c/mL) at Week 48
timeFrame: Study baseline to Week 48
measure: Change From Study Baseline in CD4 Cell Count (Cells/mm^3) at Week 48
timeFrame: Study baseline to Week 48
measure: Percentage of Participants With Confirmed Plasma HIV-1 RNA < 400 c/mL at Week 96 (Defined by FDA TLOVR Algorithm)
timeFrame: 96 Weeks
measure: Percentage of Participants With Confirmed Plasma HIV-1 RNA < 50 c/mL at Week 96 (Defined by FDA TLOVR Algorithm)
timeFrame: Week 96
measure: Percentage of Participants With Loss of Virologic Response (HIV-1 RNA < 400 c/mL) at Week 96
timeFrame: Week 96
measure: Percentage of Participants With Loss of Virologic Response (HIV-1 RNA < 50 c/mL) at Week 96
timeFrame: Week 96
measure: Percentage of Participants With Pure Virologic Failure (HIV-1 RNA < 400 c/mL) at Week 96
timeFrame: Week 96
measure: Percentage of Participants With Pure Virologic Failure (HIV-1 RNA < 50 c/mL) at Week 96
timeFrame: Week 96
measure: Change From Study Baseline in HIV-1 RNA (Log10 c/mL) at Week 96
timeFrame: Study baseline to Week 96
measure: Change From Study Baseline in CD4 Cell Count (Cells/mm^3) at Week 96
timeFrame: Baseline to Week 96
measure: Change in Limb Fat (kg) From Week 48 to Week 96
timeFrame: Week 48 to Week 96
measure: Change in Trunk Fat (kg) From Week 48 to Week 96
timeFrame: Week 48 to Week 96
measure: Change in Total Body Fat (kg) From Week 48 to Week 96
timeFrame: 48 weeks to 96 weeks
measure: Percentage of Participants With Confirmed Plasma HIV-1 RNA < 400 c/mL at Week 144 (Defined by FDA TLOVR Algorithm)
timeFrame: 144 weeks
measure: Percentage of Participants With Confirmed Plasma HIV-1 RNA < 50 c/mL at Week 144 (Defined by FDA TLOVR Algorithm)
timeFrame: Week 144
measure: Percentage of Participants With Plasma HIV-1 RNA < 400 c/mL at Week 144
timeFrame: Week 144
measure: Percentage of Participants With Plasma HIV-1 RNA < 50 c/mL at Week 144
timeFrame: Week 144
measure: Percentage of Participants With Loss of Virologic Response (HIV-1 RNA < 400 c/mL) at Week 144
timeFrame: Week 144
measure: Percentage of Participants With Loss of Virologic Response (HIV-1 RNA < 50 c/mL) at Week 144
timeFrame: Week 144
measure: Percentage of Participants With Pure Virological Failure (HIV-1 RNA < 400 c/mL) at Week 144
timeFrame: Week 144
measure: Percentage of Participants With Pure Virological Failure (HIV-1 RNA < 50 c/mL) at Week 144
timeFrame: Week 144
measure: Change From Study Baseline in HIV-1 RNA (Log10 c/mL) at Week 144
timeFrame: Study baseline to Week 144
measure: Change From Study Baseline in CD4 Cell Count (Cells/mm^3) at Week 144
timeFrame: Baseline to Week 144
measure: Change in Limb Fat (kg) From Week 48 to Week 144
timeFrame: Week 48 to Week 144
measure: Change in Trunk Fat (kg) From Week 48 to Week 144
timeFrame: Week 48 to Week 144
measure: Change in Total Body Fat (kg) From Week 48 to Week 144
timeFrame: Week 48 to Week 144
measure: Percentage of Participants With Confirmed Plasma HIV-1 RNA < 400 c/mL at Week 240 (Atripla Week 96) Defined by the FDA TLOVR Algorithm
timeFrame: Week 144 (Atripla baseline) to Week 240 (Atripla Week 96)
measure: Percentage of Participants With Confirmed Plasma HIV-1 RNA < 50 c/mL at Week 240 (Atripla Week 96) Defined by the FDA TLOVR Algorithm
timeFrame: Week 144 (Atripla baseline) to Week 240 (Atripla Week 96)
measure: Percentage of Participants With Plasma HIV-1 RNA < 400 c/mL at Week 240 (Atripla Week 96)
timeFrame: Week 240 (Atripla Week 96)
measure: Percentage of Participants With Plasma HIV-1 RNA < 50 c/mL at Week 240 (Atripla Week 96)
timeFrame: Week 240 (Atripla Week 96)
measure: Percentage of Participants With Loss of Virologic Response (HIV-1 RNA < 400 c/mL) From Week 144 (Atripla Baseline) Through Week 240 (Atripla Week 96)
timeFrame: Week 144 (Atripla Baseline) to Week 240 (Atripla Week 96)
measure: Percentage of Participants With Loss of Virologic Response (HIV-1 RNA < 50 c/mL) From Week 144 (Atripla Baseline) Through Week 240 (Atripla Week 96)
timeFrame: Week 144 (Atripla Baseline) to Week 240 (Atripla Week 96)
measure: Percentage of Participants With Pure Virological Failure (HIV-1 RNA < 400 c/mL) Through Week 240 (Atripla Week 96)
timeFrame: Week 240 (Atripla Week 96)
measure: Percentage of Participants With Pure Virological Failure (HIV-1 RNA < 50 c/mL) Through Week 240 (Atripla Week 96)
timeFrame: Week 240 (Atripla Week 96)
measure: Change From Baseline in CD4 Cell Count (Cells/mm^3) at Week 240 (Atripla Week 96)
timeFrame: Study/Atripla baseline to Week 240 (Atripla Week 96)
measure: Change in Limb Fat (kg) From Week 144 (Atripla Baseline) to Week 240 (Atripla Week 96)
timeFrame: Week 144 (Atripla Baseline) to Week 240 (Atripla Week 96)
measure: Change in Trunk Fat (kg) From Week 144 (Atripla Baseline) to Week 240 (Atripla Week 96)
timeFrame: Week 144 (Atripla Baseline) to Week 240 (Atripla Week 96)
measure: Change in Total Body Fat (kg) From Week 144 (Atripla Baseline) to Week 240 (Atripla Week 96)
timeFrame: Week 144 (Atripla Baseline) to Week 240 (Atripla Week 96)
measure: Treatment Satisfaction Questionnaire (Satisfaction With Convenience and Simplicity of Current Treatment Regimen): Change From Week 144 to Week 240 in the Category Shift From Atripla Baseline.
timeFrame: Week 144 ([W 144]; Atripla baseline) to Week 240 ([W 240]; Atripla Week 96)
measure: Treatment Satisfaction Questionnaire (Satisfaction With Current Treatment Regimen to Control HIV): Change From Week 144 to Week 240 in the Category Shift From Atripla Baseline.
timeFrame: Week 144 ([W 144]; Atripla baseline) to Week 240 ([W 240]; Atripla Week 96)
measure: Treatment Satisfaction Questionnaire (Satisfaction With Tolerability of Current Treatment Regimen) Change From Week 144 to Week 240 in the Category Shift From Atripla Baseline.
timeFrame: Week 144 ([W 144]; Atripla baseline) to Week 240 ([W 240]; Atripla Week 96)
measure: Treatment Satisfaction Questionnaire (General Satisfaction With Current Treatment Regimen): Change From Week 144 to Week 240 in the Category Shift From Atripla Baseline.
timeFrame: Week 144 ([W 144]; Atripla baseline) to Week 240 ([W 240]; Atripla Week 96)
measure: Treatment Satisfaction Questionnaire (Bothered With the Side Effects of Current Treatment Regimen): Change From Week 144 to Week 240 in the Category Shift From Atripla Baseline.
timeFrame: Week 144 ([W 144]; Atripla baseline) to Week 240 ([W 240]; Atripla Week 96)
measure: Quality of Life (SF-12v2 Health Survey: Physical Component Summary) Change From Week 144 (Atripla Baseline) to Week 240 (Atripla Week 96)
timeFrame: Week 144 (Atripla Baseline) to Week 240 (Atripla Week 96)
measure: Quality of Life (SF-12v2 Health Survey: Mental Component Summary) Change From Week 144 (Atripla Baseline) to Week 240 (Atripla Week 96)
timeFrame: Week 144 (Atripla Baseline) to Week 240 (Atripla Week 96)
Other outcomes:
Locations:
city: Beverly Hills
country: United States
facility: AIDS Healthcare Foundation Research
state: California
city: Washington
country: United States
facility: Capital Medical Associates, P.C.
state: District of Columbia
city: Orlando
country: United States
facility: Orlando Immunology Center
state: Florida
city: Chicago
country: United States
facility: NorthStar Medical Center
state: Illinois
city: Huntersville
country: United States
facility: Jemsek Clinic
state: North Carolina
Study officials:
affiliation: Gilead Sciences
name: Andrew Cheng, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Gallant JE, DeJesus E, Arribas JR, Pozniak AL, Gazzard B, Campo RE, Lu B, McColl D, Chuck S, Enejosa J, Toole JJ, Cheng AK; Study 934 Group. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med. 2006 Jan 19;354(3):251-60. doi: 10.1056/NEJMoa051871.