Clinical trial NCT00708162: Multicenter, Randomized, Double-Blind, Double-Dummy, Phase 3 Study of the Safety and Efficacy of Elvitegravir Versus Raltegravir
Official title: A Multicenter, Randomized, Double-Blind, Double-Dummy, Phase 3 Study of the Safety and Efficacy of Ritonavir-Boosted Elvitegravir (EVG/r) Versus Raltegravir (RAL) Each Administered With a Background Regimen in HIV-1 Infected, Antiretroviral Treatment-Experienced Adults
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infection
Keywords: HIV
HIV I
Treatment Experienced
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2008-07-02
Enrollment: 724
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 this study is to compare the safety, tolerability and efficacy of a regimen containing once-daily elvitegravir (EVG) versus twice-daily raltegravir (RAL) added to a background regimen (1 fully-active ritonavir (RTV)-boosted protease inhibitor (PI) plus 1 or 2 additional antiretroviral (ARV) agents) in HIV-1 infected, ARV treatment-experienced adults who have documented resistance, or at least six months experience prior to screening with two or more different classes of ARV agents.

Participants will be randomized in a 1:1 ratio to receive EVG plus background regimen (Elvitegravir group), or raltegravir plus background regimen (Raltegravir group). Due to known drug interactions, participants in the Elvitegravir group receiving RTV-boosted atazanavir (ATV) or RTV-boosted lopinavir (LPV) as part of their background regimen will receive elvitegravir at a lower dose (85 mg).

Detailed description: The background regimen will be constructed by the investigator based on viral resistance testing. The fully active PI will be defined by phenotypic resistance analysis. For phenotypic susceptibility, fully active is defined as being below the lower clinical or biological cutoff. Participants are required to take their ritonavir dose based on the dosing schedule indicated in the prescribing information for the PI; no additional ritonavir is required to be taken with EVG. No other marketed PIs are allowed as part of the background regimen due to unknown drug interactions.

The second agent can be one nucleoside or nucleotide reverse transcriptase inhibitor (NRTI), etravirine, maraviroc, or T-20. However, the second agent must not include an integrase inhibitor; the nonnucleoside reverse transcriptase inhibitors efavirenz, nevirapine, or delavirdine (due to unknown drug interactions); or the fixed-dose combination therapies Atripla® or Trizivir® (abacavir sulfate/lamivudine/zidovudine). The second agent may or may not be fully active (except in Spain, where participants have to receive a fully active second agent, as requested by the Spanish regulatory agency).

If the M184V/I reverse transcriptase (RT) mutation is present on the screening genotype report and an NRTI is used as the second agent, then either FTC or LAM may be added as a third agent in the background regimen to maintain the M184V/I mutation. In this situation only, the fixed-dose combination therapies Combivir®, Truvada®, or Epzicom/Kivexa® may be prescribed as the combined second and third agents of the background regimen.

After Week 96, participants will continue to take their blinded study drug and attend visits until treatment assignments are unblinded, at which point they will be given the option to participate in an open-label EVG extension phase of the study.

Eligibility criteria: Inclusion Criteria:

* Plasma HIV-1 RNA levels ≥ 1,000 copies/mL at screening
* Documented resistance or at least six months experience prior to screening with two or more different classes of antiretroviral agents
* Stable antiretroviral regimen for at least 30 days prior to screening: however, participants may discontinue the antiretroviral regimen after screening and remain off therapy until baseline at the discretion of the investigator
* Eligible to receive one of the fully-active ritonavir-boosted-PIs, and an allowed second agent
* Normal ECG
* Adequate renal function (estimated glomerular filtration rate according to the Cockcroft-Gault formula ≥ 60 mL/min)
* Hepatic transaminases ≤ 5 × upper limit of normal
* Total bilirubin ≤ 1.5 mg/dL, or normal direct bilirubin
* Adequate hematologic function (absolute neutrophil count ≥ 1,000/mm\^3; platelets ≥ 50,000/mm\^3; hemoglobin ≥ 8.5 g/dL)
* Serum amylase \< 1.5 × the upper limit of the normal range
* Negative serum pregnancy test (females of childbearing potential only)
* Males and females of childbearing potential must agree to use highly effective contraception methods
* Age ≥ 18 years
* Life expectancy ≥ 1 year
* Ability to understand and sign a written informed consent form

Exclusion Criteria:

* New AIDS-defining condition diagnosed within the 30 days prior to screening
* Prior treatment with any HIV-1 integrase inhibitor
* Participants experiencing ascites
* Participants experiencing encephalopathy
* Females who are breastfeeding
* Positive serum pregnancy test at any time during the study (female of childbearing potential)
* Participants receiving ongoing therapy with any disallowed medication
* Current alcohol or substance use judged by the investigator to potentially interfere with study compliance
* Malignancy other than cutaneous Kaposi's sarcoma or basal cell carcinoma
* Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or antifungal therapy within 30 days prior to baseline
* Participation in any other clinical trial (except for the etravirine or maraviroc expanded access program), without prior approval from sponsor
* Any other clinical condition or prior therapy that would make participants unsuitable for the study
* Known hypersensitivity to study drug, metabolites or formulation excipients

Primary outcomes:
measure: Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 50 Copies/mL at Week 48
timeFrame: Week 48
Secondary outcomes:
measure: Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 50 Copies/mL at Week 96
timeFrame: Week 96
measure: Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 400 Copies/mL at Week 48
timeFrame: Week 48
measure: Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 400 Copies/mL at Week 96
timeFrame: Week 96
measure: Virologic Response at Week 48 (HIV-1 RNA < 50 Copies/mL)
timeFrame: Week 48
measure: Virologic Response at Week 96 (HIV-1 RNA < 50 Copies/mL)
timeFrame: Week 96
measure: Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 50 Copies/mL) up to Week 48
timeFrame: Baseline to Week 48
measure: Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 50 Copies/mL) up to Week 96
timeFrame: Baseline to Week 96
measure: Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 400 Copies/mL) up to Week 48
timeFrame: Baseline to Week 48
measure: Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 400 Copies/mL) up to Week 96
timeFrame: Baseline to Week 96
measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48
timeFrame: Week 48
measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 96
timeFrame: Week 96
measure: Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Week 48
timeFrame: Week 48
measure: Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Week 96
timeFrame: Week 96
measure: Change From Baseline in HIV-1 RNA at Week 48
timeFrame: Baseline to Week 48
measure: Change From Baseline in HIV-1 RNA at Week 96
timeFrame: Baseline to Week 96
measure: Change From Baseline in CD4 Cell Count at Week 48
timeFrame: Baseline to Week 48
measure: Change From Baseline in CD4 Cell Count at Week 96
timeFrame: Baseline to Week 96
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Southwest Center for HIV/AIDS
state: Arizona
city: Little Rock
country: United States
facility: Health for Life Clinic, PLLC
state: Arkansas
city: Beverly Hills
country: United States
facility: Pacific Oaks Medical Group
state: California
city: Beverly Hills
country: United States
facility: AIDS Healthcare Foundation-Research Center
state: California
city: Fountain Valley
country: United States
facility: Center for Special Immunology
state: California
city: Long Beach
country: United States
facility: The Living Hope Foundation
state: California
city: Los Angeles
country: United States
facility: Kaiser Permanente
state: California
city: Los Angeles
country: United States
facility: Jeffrey Goodman Special Care Clinic
state: California
city: Los Angeles
country: United States
facility: University of Southern California, AIDS Clinical Trials Unit
state: California
city: Los Angeles
country: United States
facility: Peter J. Ruane, MD, Inc.
state: California
city: Los Angeles
country: United States
facility: Tony Mills, MD Internal Medicine
state: California
city: Newport Beach
country: United States
facility: Orange Coast Medical Group
state: California
city: Oakland
country: United States
facility: Alameda County Medical Center
state: California
city: Oakland
country: United States
facility: East Bay AIDS Center
state: California
city: Sacramento
country: United States
facility: Kaiser Permanente
state: California
city: San Diego
country: United States
facility: David J. Shamblaw, MD Inc.
state: California
city: San Francisco
country: United States
facility: Metropolis Medical
state: California
city: San Francisco
country: United States
facility: San Francisco VA Medical Center/UCSF
state: California
city: Glastonbury
country: United States
facility: Connecticut Health Care Group
state: Connecticut
city: Norwalk
country: United States
facility: Circle Medical LLC
state: Connecticut
city: Stamford
country: United States
facility: The Stamford Hospital - Stamford ID
state: Connecticut
city: Washington
country: United States
facility: Whitman-Walker Clinic
state: District of Columbia
city: Washington
country: United States
facility: The George Washington University Medical Center
state: District of Columbia
city: Atlantis
country: United States
facility: South Florida Clinical Research
state: Florida
city: Fort Lauderdale
country: United States
facility: Lifeway , Inc.
state: Florida
city: Fort Lauderdale
country: United States
facility: NorthPoint Medical
state: Florida
city: Fort Lauderdale
country: United States
facility: Therafirst Medical Centers
state: Florida
city: Fort Lauderdale
country: United States
facility: Broward Health CCC
state: Florida
city: Fort Lauderdale
country: United States
facility: Gary Richmond, MD, PA, Inc.
state: Florida
city: Fort Pierce
country: United States
facility: Associates In Infectious Diseases
state: Florida
city: Miami
country: United States
facility: The Kinder Medical Group
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: North Miami Beach
country: United States
facility: Wohlfeiler, Piperato and Associates, LLC
state: Florida
city: Orlando
country: United States
facility: Orlando Immunology Center
state: Florida
city: Orlando
country: United States
facility: Infectious Disease of Central Florida
state: Florida
city: Safety Harbor
country: United States
facility: Barry M. Rodwick, M. D.
state: Florida
city: Tampa
country: United States
facility: St. Joseph's Comprehensive Research Institute
state: Florida
city: Vero Beach
country: United States
facility: Treasure Coast Infectious Disease Consultants
state: Florida
city: Atlanta
country: United States
facility: AIDS Research Consortium of Atlanta
state: Georgia
city: Atlanta
country: United States
facility: The Emory Clinic, Inc., Division of Infectious Diseases
state: Georgia
city: Atlanta
country: United States
facility: Atlanta ID Group
state: Georgia
city: Decatur
country: United States
facility: Infectious Disease Specialists of Atlanta (IDSA)
state: Georgia
city: Macon
country: United States
facility: Mercer Univ. School of Medicine
state: Georgia
city: Savannah
country: United States
facility: Chatham County Health Department
state: Georgia
city: Honolulu
country: United States
facility: Hawaii AIDS Clinical Research Program HACRP
state: Hawaii
city: Chicago
country: United States
facility: The Ruth M. Rothstein CORE Center
state: Illinois
city: Chicago
country: United States
facility: Howard Brown Health Center
state: Illinois
city: Chicago
country: United States
facility: Northstar Medical Center
state: Illinois
city: Lexington
country: United States
facility: University of Kentucky Healthcare/Bluegrass Care Clinic
state: Kentucky
city: Baltimore
country: United States
facility: University of Maryland, Institute of Human Virology
state: Maryland
city: Boston
country: United States
facility: Community Research Initiative of New England
state: Massachusetts
city: Berkley
country: United States
facility: Be Well Medical Center
state: Michigan
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital Div of Infectious Disease
state: Michigan
city: St. Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: St. Louis
country: United States
facility: Southampton Healthcare, Inc.
state: Missouri
city: Hillsborough
country: United States
facility: ID Care
state: New Jersey
city: Newark
country: United States
facility: Saint Michael's Medical Center
state: New Jersey
city: Newark
country: United States
facility: University of Medicine and Dentistry of New Jersey; University Hospital Infectious Disease Practice
state: New Jersey
city: Somer Point
country: United States
facility: South Jersey Infectious Disease
state: New Jersey
city: Santa Fe
country: United States
facility: Southwest C.A.R.E. Center
state: New Mexico
city: Albany
country: United States
facility: Albany Medical College
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Brooklyn
country: United States
facility: STAR Health Care Center
state: New York
city: Mt. Vernon
country: United States
facility: Greiger Clinic
state: New York
city: New York
country: United States
facility: Beth Israel Medical Center
state: New York
city: New York
country: United States
facility: Chelsea Village Medical, PC
state: New York
city: New York
country: United States
facility: Ricky K. Hsu, MD, PC
state: New York
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: Rochester
country: United States
facility: AIDS Community HealthCenter
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina/ School of Medicine Division of Infectious Diseases/ AIDS Clinical Trials Unit
state: North Carolina
city: Charlotte
country: United States
facility: Carolinas Medical Center
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Greenville
country: United States
facility: Brody School of Medicine at East Carolina University
state: North Carolina
city: Huntersville
country: United States
facility: Rosedale Infectious Diseases
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Akron
country: United States
facility: Summa Health CARE Center
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Philadelphia FIGHT
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Jefferson Alumni Hall
state: Pennsylvania
city: Austin
country: United States
facility: Central Texas Clinical Research
state: Texas
city: Dallas
country: United States
facility: AIDS Arms/ Peabody Health Center
state: Texas
city: Dallas
country: United States
facility: Southwest Infectious Disease Clinical Research
state: Texas
city: Dallas
country: United States
facility: Presbyterian Hospital of Dallas
state: Texas
city: Dallas
country: United States
facility: North Texas Infectious Disease Consultants
state: Texas
city: Fort Worth
country: United States
facility: Tarrant County Infectious Disease Associates
state: Texas
city: Harlingen
country: United States
facility: Garcia Family Health Group
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science Center at Houston
state: Texas
city: Houston
country: United States
facility: Gordon E. Crofoot, MD, PA
state: Texas
city: Houston
country: United States
facility: The Schrader Clinic
state: Texas
city: Houston
country: United States
facility: Joseph C. Gathe, JR. MD, F.A.C.P.
state: Texas
city: Longview
country: United States
facility: DCOL Center for Clinical Research
state: Texas
city: Annandale
country: United States
facility: Clinical Alliance for Research & Education - Infectious Diseases, LLC (CARE-ID)
state: Virginia
city: Spokane
country: United States
facility: EHS Pulmonary and Critical Care
state: Washington
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Darlinghurst
country: Australia
facility: Ground Zero Medical Centre
state: New South Wales
city: Darlinghurst
country: Australia
facility: Holdsworth House Medical Practice
state: New South Wales
city: Darlinghurst
country: Australia
facility: St. Vincent's Hospital, Sydney
state: New South Wales
city: Kogarah
country: Australia
facility: St George Hospital
state: New South Wales
city: Sidney
country: Australia
facility: East Sidney Doctors
state: New South Wales
city: Sydney
country: Australia
facility: Albion Street Centre
state: New South Wales
city: Wentworthville
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Antwerp
country: Belgium
facility: Institute of Tropical Medicine
city: Brussels
country: Belgium
facility: C.H.U. St Pierre
city: Brussels
country: Belgium
facility: Hôpital Erasme
city: Charleroi
country: Belgium
facility: CHU de Charleroi-Hopital civil
city: Liege
country: Belgium
facility: Centre Hospitalier Universitaire de Liège
city: Vancouver
country: Canada
facility: Downtown Infectious Diseases Clinic
state: British Columbia
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Centre
state: Nova Scotia
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: CascAids Research
state: Ontario
city: Toronto
country: Canada
facility: Canadian Immunodeficiency Research Collaborative (CIRC) Inc.
state: Ontario
city: Toronto
country: Canada
facility: University Health Network, Toronto General Hospital
state: Ontario
city: Montreal
country: Canada
facility: Clinique medicale l'Actuel
state: Quebec
city: Montreal
country: Canada
facility: Immunodeficiency Service, McGill University Health Centre (MUHC)
state: Quebec
city: Winnipeg
country: Canada
facility: University of Manitoba - Health Sciences Centre
city: Le Kremlin Bicetre
country: France
facility: Hopital de Bicentre - Service de medecine Interne et Immunologie
city: Montpellier
country: France
facility: University Hospital of Montpellier - Gui de Chauliac
city: Nantes
country: France
facility: CHU Nantes
city: Nice
country: France
facility: C.H.U. de Nice - Hopital de l'Archet 1
city: Paris
country: France
facility: Hopital Saint Louis
city: Paris
country: France
facility: Hopital Saint Antoine - Infectious Desease Department
city: Paris
country: France
facility: Hopital Pitie Salpetriere - Infectious Deseases Department
city: Paris
country: France
facility: APHP Hopital Bichat-Claude Bernard
city: Paris
country: France
facility: Hopital Tenon
city: Pessac
country: France
facility: CHU Bordeaux
city: Toulouse
country: France
facility: Hopital Purpan - Service of Infectious Diseases
city: Bonn
country: Germany
facility: Universitatsklinikum Bonn
city: Dusseldorf
country: Germany
facility: Universitatsklinikum Dusseldorf
city: Essen
country: Germany
facility: Universitatklinikum Essen
city: Frankfurt
country: Germany
facility: Klinikum der J.W. Goethe-Universitat
city: Hamburg
country: Germany
facility: IFI-Institute
city: Hamburg
country: Germany
facility: Ambulanzzentrum am Universitatsklinikum Hamburg Eppendorf
city: Kiel
country: Germany
facility: Medizinische Universitatsklinik Kiel
city: Koln
country: Germany
facility: Klinikum der Universitat zu Koln
city: Munich
country: Germany
facility: MUC Research
city: Bergamo
country: Italy
facility: Ospedali Riuniti Di Bergamo
city: Brescia
country: Italy
facility: Spedali Civili di Brescia
city: Milan
country: Italy
facility: Fondazione Centro San Raffaele del Monte Tabor
city: Milan
country: Italy
facility: Ospedale L. Sacco
city: Milan
country: Italy
facility: Ospedale Luigi Sacco
city: Rome
country: Italy
facility: Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani I.R.C.C.S.
city: Rome
country: Italy
facility: Universita La Sapienza Policlinico Umberto I
city: Rome
country: Italy
facility: Universita' Cattolica Del Sacro Cuore
city: Mexico
country: Mexico
facility: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran (INCMYNSZ)
state: D.f.
city: Leon
country: Mexico
facility: Hospital Regional de Leon Guanajuato
state: Guanajuato
city: Guadalajara
country: Mexico
facility: Hospital Civil de Guadalajara
state: Jalisco
city: San Luis Potosi
country: Mexico
facility: Hospital Central Morones Prieto
state: San Luis Potsi
city: Rotterdam
country: Netherlands
facility: Erasmus Medisch Centrum
city: Amadora
country: Portugal
facility: Hospital Fernando Fonseca
city: Lisbon
country: Portugal
facility: Hospital Santo Antonio dos Capuchos
city: Lisbon
country: Portugal
facility: Hospital de Santa Maria
city: Lisbon
country: Portugal
facility: Hospital Pulido Valente
city: Porto
country: Portugal
facility: Hospital de Sao Joao
city: Ponce
country: Puerto Rico
facility: Instituto de Investigacion Cientifica del Sur
city: San Juan
country: Puerto Rico
facility: Clinical Research Puerto Rico, Inc.
city: San Juan
country: Puerto Rico
facility: HOPE Clinical Research
city: San Juan
country: Puerto Rico
facility: VA Caribbean healthcare System
city: San Juan
country: Puerto Rico
facility: University of Puerto Rico, School of Medicine, Proyecto ACTU
city: Alicante
country: Spain
facility: Hospital General Universitario de Alicante
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial de Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitario Germans Trias i Pujol
city: Cordoba
country: Spain
facility: Hospital Reina Sofia
city: Elche
country: Spain
facility: Hospital General Universitario del Elche
city: Granada
country: Spain
facility: Hospital Clinico San Cecilio
city: Madrid
country: Spain
facility: Hospital La Princesa
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Doce De Octubre
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Malaga
country: Spain
facility: Hospital Virgen de la Victoria
city: Santa Cruz de Tenerife
country: Spain
facility: Hospital Universitario de Canarias
city: Sevilla
country: Spain
facility: Hospital Virgen del Rocio
city: Vigo
country: Spain
facility: Complexo Hospitalario Xeral-Cies (Chuvi) Vigo
city: Zurich
country: Switzerland
facility: Universitatsspital Zurich
city: Edinburgh
country: United Kingdom
facility: RIDU, Western General Hospital
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust, St. Mary's Campus
city: London
country: United Kingdom
facility: Royal Free and University College Medical School
city: Manchester
country: United Kingdom
facility: North Manchester General Hospital
Study officials:
affiliation: Gilead Sciences
name: Javier Szwarcberg, MD, MPH
role: STUDY_DIRECTOR
References:
citation: Molina JM, Lamarca A, Andrade-Villanueva J, Clotet B, Clumeck N, Liu YP, Zhong L, Margot N, Cheng AK, Chuck SL; Study 145 Team. Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: randomised, double-blind, phase 3, non-inferiority study. Lancet Infect Dis. 2012 Jan;12(1):27-35. doi: 10.1016/S1473-3099(11)70249-3. Epub 2011 Oct 18.