Clinical trial NCT00440947: Induction/Simplification With Atazanavir + Ritonavir + Abacavir/Lamivudine Fixed-Dose Combination In HIV-1 Infection
Official title: See Detailed Description
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Infection, Human Immunodeficiency Virus I
HIV Infection
Keywords: NORVIR
ARIES
EPZICOM
REYATAZ
HIV
simplification
Antiretroviral-naive
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: GlaxoSmithKline
First posted: 2007-02-27
Enrollment: 515
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: This study was designed to test the efficacy, safety, tolerability and durability of the antiviral response between atazanavir (ATV) + ritonavir (/r) + abacavir/lamivudine(ABC/3TC) Fixed dose combination (FDC) each administered once daily (QD) for 36 weeks followed by randomization to either a simplification regimen of ATV or continuation of ATV +/r for an additional 48 weeks, each in combination with ABC/3TC in antiretroviral (ART)-naive, HIV-1 infected, HLA-B\*5701 negative subjects.

All subjects who complete the 84-week study will be eligible to enter the treatment extension phase and continue for an additional 60 weeks. The purpose of this extension is to obtain longer term treatment data in subjects who have completed the 84-week study.

Detailed description: Safety and Efficacy of an Initial Regimen of Atazanavir (ATV) + Ritonavir (/r) + the Abacavir/Lamivudine Fixed-Dose Combination Tablet (ABC/3TC FDC) for 36 weeks followed by Simplification to Atazanavir with ABC/3TC FDC or Maintenance of the Initial Regimen for an Additional 48 weeks in Antiretroviral-Naive HIV-1 Infected HLA-B\*5701 Negative Subjects followed by an Optional 60-Week Treatment Extension Phase

Eligibility criteria: Inclusion criteria:

* Subject is ≥ 18 years of age and has documented evidence of HIV-1 infection. (A female is eligible to enter and participate in this study if she is of: non child-bearing potential, child bearing potential with a negative pregnancy test and agrees to approved contraception methods, or agreement for complete abstinence.)
* Subject is antiretroviral-naïve (defined as having ≤14 days of prior therapy with any NRTI and no prior therapy with either a PI or NNRTI).
* Subject has plasma HIV-1 RNA ≥ 1,000 copies/mL by Roche COBAS AMPLICOR™ (Version 1.5) method at screening (if no other documentation of HIV infection is available, a positive result here may serve as documentation of HIV infection for this study).
* Subject is willing and able to understand and provide written informed consent prior to participation in this study.

Exclusion criteria:

* Subject is HLA-B\*5701 positive.
* Subject testing positive for Hepatitis B or both Hepatitis B and Hepatitis C at screening (+ HbsAg)
* Genotyping results performed at the screening indicate that the subject has any of the following mutations at the reverse transcriptase (RT) enzyme: K65R, L74V, or Y115F, or a combination of two or more thymidine analog mutations (M41L, D67N, K70R, K219Q or E) that include changes at either L210 or T215, or ≥ 3 of the following protease mutations associated with atazanavir resistance: D30, V32, M36, M46, I47, G48, I50, I54, A71, G73, V77, V82, I84, N88, and L90.
* Women who are pregnant or breastfeeding.
* Subject has an active or acute CDC Clinical Category C event at screening. Treatment for the acute event must have been completed at least 30 days prior to screening.
* Subject is, in the opinion of the investigator, unable to complete the 84-week dosing period and protocol evaluations and assessments.
* Subject has ongoing clinically relevant pancreatitis or clinically relevant hepatitis at screening.
* Presence of a newly diagnosed HIV-related opportunistic infection or any medical condition requiring acute therapy at the time of enrollment.
* Subject suffers from a serious medical condition, such as diabetes, congestive heart failure, cardiomyopathy or other cardiac dysfunction (including known, clinically significant cardiac conduction system disease, severe first degree atrioventricular block \[PR interval \> 0.26 seconds\], second or third-degree atrioventricular block), which in the opinion of the investigator would compromise the safety of the subject.
* Subject has pre-existing mental, physical, or substance abuse disorder, which in the opinion of the investigator would interfere with the subject's ability to comply with the dosing schedule and protocol evaluations and assessments.
* Subject has a history of inflammatory bowel disease or malignancy, intestinal ischemia, malabsorption, or other gastrointestinal dysfunction, which may interfere with drug absorption or render the subject unable to take oral medication.
* Subject requires treatment with foscarnet, hydroxyurea or other agents with documented activity against HIV-1 in vitro within 28 days of study administration.
* Subject requires treatment with immunomodulating agents (such as systemic corticosteroids, interleukins, vaccines, or interferons) within 28 days prior to screening, or subject had received an HIV-1 immunotherapeutic vaccine within 90 days prior to screening. Subjects using inhaled corticosteroids are eligible for enrollment.
* Creatinine clearance \<50 mL/min via the Cockroft-Gault method \[Cockroft, 1976\].
* Active alcohol or substance use sufficient, in the investigator's opinion, to prevent adequate compliance with study therapy or to increase the risk of developing pancreatitis or chemical hepatitis.
* Hypersensitivity to any component of the study drugs.
* Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>5 times the upper limit of normal (ULN).
* Total bilirubin \> 1.5 times the upper limit of normal (ULN).
* Subject has any acute laboratory abnormality at screening, which, in the opinion of the investigator, would preclude the subject's participation in the study of an investigational compound. Any grade 4 laboratory abnormality would exclude a subject from study participation.
* Subject requires treatment with radiation therapy or cytotoxic chemotherapeutic agents within 28 days prior to screening, or has an anticipated need for these agents within the study period.
* Enrolled in one or more investigational drug protocols, which may have impacted HIV-1 RNA suppression.
* Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study.
* Subjects requiring concomitant administration of proton pump inhibitors.
* Subjects who require treatment with the prohibited medications within 28 days of commencement of investigational product, or an anticipated need during the study.

Eligibility Criteria for Treatment Extension Phase:

-Subjects will be eligible to continue in the treatment extension phase (Weeks 84 to 144) if they have successfully completed the 84-week study.

Primary outcomes:
measure: Percentage of Participants (PAR) Who Achieved Plasma HIV-1 RNA <50 Copies (c) /Milliliter (ml) at the Week 84 Visit
timeFrame: Week 84
Secondary outcomes:
measure: Mean Age at Baseline of Participants Randomized to Treatment for the 48-Week Randomized Phase
timeFrame: Baseline of Randomized Phase
measure: Percentage of Participants Who Achieved Plasma HIV-1 RNA <50 c/ml at the Week 36 Visit
timeFrame: Week 36
measure: Percentage of Participants Who Achieved Plasma HIV-1 RNA <50 c/ml at the Week 84 Visit
timeFrame: Week 84
measure: Percentage of Participants Who Achieved Plasma HIV-1 RNA <50 c/ml at the Week 144 Visit
timeFrame: Week 144
measure: Percentage of Participants Who Achieved Plasma HIV-1 RNA <400 c/ml at the Week 36 Visit
timeFrame: Week 36
measure: Percentage of Participants Who Achieved HIV-1 RNA <400 c/ml at the Week 84 Visit
timeFrame: Week 84
measure: Percentage of Participants Who Achieved HIV-1 RNA <400 c/ml at the Week 144 Visit
timeFrame: Week 144
measure: Number of Participants Who Met the Protocol-defined Virologic Failure (PDVF) Criteria at Week 36
timeFrame: Week 36
measure: Number of Participants Who Met the PDVF Criteria at Week 84
timeFrame: Week 84
measure: Number of Participants Who Met the PDVF Criteria at Week 144
timeFrame: Week 144
measure: Change From Baseline in HIV-1 RNA at Week 36
timeFrame: Baseline and Week 36
measure: Change From Baseline in HIV-1 RNA at Week 84
timeFrame: Baseline and Week 84
measure: Change From Baseline in HIV-1 RNA at Week 144
timeFrame: Baseline and Week 144
measure: Change From Baseline in CD4+ Cell Count at Week 36
timeFrame: Baseline and Week 36
measure: Change From Baseline in CD4+ Cell Count at Week 84
timeFrame: Baseline and Week 84
measure: Change From Baseline in CD4+ Cell Count at Week 144
timeFrame: Baseline and Week 144
measure: Number of Confirmed Virologic Failure Participants With Treatment-emergent HIV Genotypic Resistance in Reverse Transcriptase and Protease From Baseline Through Week 36
timeFrame: Baseline through Week 36
measure: Number of Confirmed Virologic Failure Participants With Treatment-emergent HIV Genotypic Resistance in Reverse Transcriptase and Protease From Randomization at Week 36 Through Week 84
timeFrame: Randomization at Week 36 through Week 84
measure: Number of Confirmed Virologic Failure Participants With Treatment-emergent HIV Genotypic Resistance in Reverse Transcriptase and Protease From Week 84 Through Week 144
timeFrame: Week 84 through Week 144
measure: Number of Confirmed Virologic Failure Participants From Baseline Through Week 36 With Treatment-emergent Reductions in Susceptibility to Abacavir, Lamivudine, Atazanavir, or Ritonavir
timeFrame: Baseline through Week 36
measure: Number of Confirmed Virologic Failure Participants From Randomization at Week 36 Through Week 84 With Treatment-emergent Reductions in HIV Susceptibility to Abacavir, Lamivudine, Atazanavir, or Ritonavir
timeFrame: Randomization at Week 36 through Week 84
measure: Number of Confirmed Virologic Failure Participants From Week 84 Through Week 144 With Treatment-emergent Reductions in HIV Susceptibility to Abacavir, Lamivudine, Atazanavir, or Ritonavir
timeFrame: Week 84 through Week 144
measure: Mean Percent Compliance at Week 36
timeFrame: Week 36
measure: Mean Percent Compliance at Week 84
timeFrame: Week 84
measure: Mean Percent Compliance at Week 144
timeFrame: Week 144
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: GSK Investigational Site
state: Arizona
city: Long Beach
country: United States
facility: GSK Investigational Site
state: California
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: Newport Beach
country: United States
facility: GSK Investigational Site
state: California
city: Oakland
country: United States
facility: GSK Investigational Site
state: California
city: Denver
country: United States
facility: GSK Investigational Site
state: Colorado
city: Glastonbury
country: United States
facility: GSK Investigational Site
state: Connecticut
city: Washington
country: United States
facility: GSK Investigational Site
state: District of Columbia
city: Washington
country: United States
facility: GSK Investigational Site
state: District of Columbia
city: Washington
country: United States
facility: GSK Investigational Site
state: District of Columbia
city: Washington
country: United States
facility: GSK Investigational Site
state: District of Columbia
city: Fort Lauderdale
country: United States
facility: GSK Investigational Site
state: Florida
city: Fort Lauderdale
country: United States
facility: GSK Investigational Site
state: Florida
city: Fort Pierce
country: United States
facility: GSK Investigational Site
state: Florida
city: Ft. Lauderdale
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
city: Plantation
country: United States
facility: GSK Investigational Site
state: Florida
city: Sarasota
country: United States
facility: GSK Investigational Site
state: Florida
city: Tampa
country: United States
facility: GSK Investigational Site
state: Florida
city: Tampa
country: United States
facility: GSK Investigational Site
state: Florida
city: Atlanta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Atlanta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Atlanta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Augusta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Decatur
country: United States
facility: GSK Investigational Site
state: Georgia
city: Chicago
country: United States
facility: GSK Investigational Site
state: Illinois
city: Chicago
country: United States
facility: GSK Investigational Site
state: Illinois
city: Maywood
country: United States
facility: GSK Investigational Site
state: Illinois
city: Lexington
country: United States
facility: GSK Investigational Site
state: Kentucky
city: Baltimore
country: United States
facility: GSK Investigational Site
state: Maryland
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Detroit
country: United States
facility: GSK Investigational Site
state: Michigan
city: Minneapolis
country: United States
facility: GSK Investigational Site
state: Minnesota
city: Minneapolis
country: United States
facility: GSK Investigational Site
state: Minnesota
city: St. Louis
country: United States
facility: GSK Investigational Site
state: Missouri
city: Hillsborough
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Newark
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Somers Point
country: United States
facility: GSK Investigational Site
state: New Jersey
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Valhalla
country: United States
facility: GSK Investigational Site
state: New York
city: Charlotte
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Greenville
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Akron
country: United States
facility: GSK Investigational Site
state: Ohio
city: Toledo
country: United States
facility: GSK Investigational Site
state: Ohio
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Providence
country: United States
facility: GSK Investigational Site
state: Rhode Island
city: Austin
country: United States
facility: GSK Investigational Site
state: Texas
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: El Paso
country: United States
facility: GSK Investigational Site
state: Texas
city: Fort Worth
country: United States
facility: GSK Investigational Site
state: Texas
city: Galveston
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Longview
country: United States
facility: GSK Investigational Site
state: Texas
city: Annandale
country: United States
facility: GSK Investigational Site
state: Virginia
city: Norfolk
country: United States
facility: GSK Investigational Site
state: Virginia
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Ponce
country: Puerto Rico
facility: GSK Investigational Site
city: Ponce
country: Puerto Rico
facility: GSK Investigational Site
city: San Juan
country: Puerto Rico
facility: GSK Investigational Site
city: San Juan
country: Puerto Rico
facility: GSK Investigational Site
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: L Ross, E Dejesus, M Potter, A LaMarca, D Murphy, I Melendez-Rivera, D Ward, P Wannamaker, J Uy, L Patel, H Amrine-Madsen, J Horton. Epidemiological and Genotypic Clustering of HIV infection within North America During 2007 International HIV & Hepatitis Drug Resistance Workshop & Curative Strategies, 8-12 June 2010, Dubrovnik, Croatia, Poster 150.
citation: Young B, Squires K, Patel P, Dejesus E, Bellos N, Berger D, Sutherland-Phillips DH, Liao Q, Shaefer M, Wannamaker P. First large, multicenter, open-label study utilizing HLA-B*5701 screening for abacavir hypersensitivity in North America. AIDS. 2008 Aug 20;22(13):1673-5. doi: 10.1097/QAD.0b013e32830719aa.
citation: • L Ross, K Squires, B Young, E DeJesus, N Bellos, D Murphy, A Rachlis, H Zhao, L Patel, L Ross, P Wannamaker, M Shaefer. Genotypic Screening Impact in ARIES [Atazanavir (ATV) + Ritonavir (/r) + Abacavir/Lamivudine (ABC/3TC) for 36 Weeks Followed By Randomization to ATV +ABC/3TC or ATV/r + ABC/3TC for 48 Wks in HIV-infected, ART Naïve Patients] :Low Rates of Virologic Failure. The 19th Annual Canadian Conference on HIV/AIDS Research, 13-16 May 2010, Saskatoon, Canada. Poster P-169.
citation: K Squires, E DeJesus, N Bellos, D Ward, D Murphy, H Zhao, L Patel, L Ross, P Wannamaker, M Shaefer. Sustained Virologic Efficacy of Atazanavir (ATV) Versus Atazanavir/Ritonavir (ATV/r), each in Combination with Abacavir/Lamivudine (ABC/3TC) over 120 Weeks: the ARIES Trial. 48th ICAAC; September 12-15, 2010, Boston, MA. Poster H-204.
citation: K Squires, B Young, E DeJesus, N Bellos, D Murphy, D Sutherland-Phillips, H Zhao, L Patel, L Ross, P Wannamaker, M Shaefer. Atazanavir/Ritonavir (ATV/r) + Abacavir/Lamivudine (ABC/3TC) in Antiretroviral (ART)-Naive HIV-1 Infected HLA-B*5701 Negative Subjects Demonstrates Efficacy and Safety: the ARIES Trial. 48th ICAAC; October 25-28, 2008, Washington, DC. Poster H-1250a.
citation: K Squires, B Young, E DeJesus, N Bellos, D Murphy, D Sutherland-Phillips, H Zhao, L Patel, L Ross, P Wannamaker, M Shaefer. Similar Efficacy and Tolerability of Atazanavir (ATV) Compared to ATV/Ritonavir (RTV, r), Each in Combination with Abacavir/Lamivudine (ABC/3TC), after Initial Suppression with ABC/3TC + ATV/r in HIV-1 Infected Patients: 84 Week Results of the ARIES Trial. 5th IAS Conference; Cape Town, South Africa. Abstract WELBB103
citation: Squires KE, Young B, DeJesus E, Bellos N, Murphy D, Sutherland-Phillips DH, Zhao HH, Patel LG, Ross LL, Wannamaker PG, Shaefer MS; ARIES Study Team. Safety and efficacy of a 36-week induction regimen of abacavir/lamivudine and ritonavir-boosted atazanavir in HIV-infected patients. HIV Clin Trials. 2010 Mar-Apr;11(2):69-79. doi: 10.1310/hct1102-69.
citation: Squires KE, Young B, Dejesus E, Bellos N, Murphy D, Zhao HH, Patel LG, Ross LL, Wannamaker PG, Shaefer MS; ARIES study team. Similar efficacy and tolerability of atazanavir compared with atazanavir/ritonavir, each with abacavir/lamivudine after initial suppression with abacavir/lamivudine plus ritonavir-boosted atazanavir in HIV-infected patients. AIDS. 2010 Aug 24;24(13):2019-27. doi: 10.1097/QAD.0b013e32833bee1b.
citation: Ross LL, Horton J, Hasan S, Brown JR, Murphy D, DeJesus E, Potter M, LaMarca A, Melendez-Rivera I, Ward D, Uy J, Shaefer MS. HIV-1 transmission patterns in antiretroviral therapy-naive, HIV-infected North Americans based on phylogenetic analysis by population level and ultra-deep DNA sequencing. PLoS One. 2014 Feb 26;9(2):e89611. doi: 10.1371/journal.pone.0089611. eCollection 2014.
citation: Squires KE, Young B, DeJesus E, Bellos N, Murphy D, Ward D, Zhao HH, Ross LL, Shaefer MS; ARIES Study Team. ARIES 144 week results: durable virologic suppression in HIV-infected patients simplified to unboosted atazanavir/abacavir/lamivudine. HIV Clin Trials. 2012 Sep-Oct;13(5):233-44. doi: 10.1310/hct1305-233.
citation: Young B, Squires KE, Ross LL, Santiago L, Sloan LM, Zhao HH, Wine BC, Pakes GE, Margolis DA, Shaefer MS; Aries EPZ108859 Study Team. Inflammatory biomarker changes and their correlation with Framingham cardiovascular risk and lipid changes in antiretroviral-naive HIV-infected patients treated for 144 weeks with abacavir/lamivudine/atazanavir with or without ritonavir in ARIES. AIDS Res Hum Retroviruses. 2013 Feb;29(2):350-8. doi: 10.1089/aid.2012.0278. Epub 2012 Dec 5.