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Multicenter, Randomized, Double-Blind, Double-Dummy, Phase 3 Study of the Safety and Efficacy of Elvitegravir Versus Raltegravir

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT00708162
First received: June 30, 2008
Last updated: October 30, 2014
Last verified: October 2014
  Purpose

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 added to a background regimen (containing a fully-active ritonavir-boosted protease inhibitor [PI/r] and a second agent) in HIV-1 infected, antiretroviral treatment-experienced adults who have documented resistance, or at least six months experience prior to screening with two or more different classes of antiretroviral agents.

Participants will be randomized in a 1:1 ratio to receive EVG plus background regimen (elvitegravir arm), or raltegravir plus background regimen (raltegravir arm).


Condition Intervention Phase
HIV Infection
Drug: Elvitegravir
Drug: Raltegravir
Drug: Placebo to match elvitegravir
Drug: Placebo to match raltegravir
Drug: Background regimen
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Gilead Sciences:

Primary Outcome Measures:
  • Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 50 Copies/mL at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    The percentage of participants achieving and maintaining confirmed HIV-1 RNA < 50 copies/mL at Week 48 was analyzed using the FDA-defined Time to Loss of Virologic Response (TLOVR) algorithm, which takes into account a patient's longitudinal viral load up to the predefined time point by considering patterns of suppression and rebounding.


Secondary Outcome Measures:
  • Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 50 Copies/mL at Week 96 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    The percentage of participants achieving and maintaining confirmed HIV-1 RNA < 50 copies/mL at Week 96 was analyzed using the FDA-defined TLOVR algorithm, which takes into account a patient's longitudinal viral load up to the predefined time point by considering patterns of suppression and rebounding.

  • Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 400 Copies/mL at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    The percentage of participants achieving and maintaining confirmed HIV-1 RNA < 400 copies/mL at Week 48 was analyzed using the FDA-defined TLOVR algorithm, which takes into account a patient's longitudinal viral load up to the predefined time point by considering patterns of suppression and rebounding.

  • Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 400 Copies/mL at Week 96 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    The percentage of participants achieving and maintaining confirmed HIV-1 RNA < 400 copies/mL at Week 96 was analyzed using the FDA-defined TLOVR algorithm, which takes into account a patient's longitudinal viral load up to the predefined time point by considering patterns of suppression and rebounding.

  • Virologic Response at Week 48 (HIV-1 RNA < 50 Copies/mL) [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    Virologic response at Week 48 (percentage of participants with HIV-1 RNA < 50 copies/mL) was analyzed using the FDA-defined TLOVR algorithm, which takes into account a patient's longitudinal viral load up to the predefined time point by considering patterns of suppression and rebounding.

  • Virologic Response at Week 96 (HIV-1 RNA < 50 Copies/mL) [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    Virologic response at Week 96 (percentage of participants with HIV-1 RNA < 50 copies/mL) was analyzed using the FDA-defined Snapshot algorithm, which defines a patient's virologic response status using only the viral load at the predefined time point within an allowed window of time.

  • Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 50 Copies/mL) up to Week 48 [ Time Frame: Baseline to Week 48 ] [ Designated as safety issue: No ]
    The percentage of participants with pure virologic failure (HIV-1 RNA cutoff at 50 copies/mL) up to Week 48 was estimated using the Kaplan-Meier method in the time to event analysis.

  • Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 50 Copies/mL) up to Week 96 [ Time Frame: Baseline to Week 96 ] [ Designated as safety issue: No ]
    The percentage of participants with pure virologic failure (HIV-1 RNA cutoff at 50 copies/mL) up to Week 96 was estimated using the Kaplan-Meier method in the time to event analysis.

  • Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 400 Copies/mL) up to Week 48 [ Time Frame: Baseline to Week 48 ] [ Designated as safety issue: No ]
    The percentage of participants with pure virologic failure (HIV-1 RNA cutoff at 400 copies/mL) up to Week 48 was estimated using the Kaplan-Meier method in the time to event analysis.

  • Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 400 Copies/mL) up to Week 96 [ Time Frame: Baseline to Week 96 ] [ Designated as safety issue: No ]
    The percentage of participants with pure virologic failure (HIV-1 RNA cutoff at 400 copies/mL) up to Week 96 was estimated using the Kaplan-Meier method in the time to event analysis.

  • Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 48 was analyzed using the missing = failure method, where participants with missing data were considered as having failed to meet the criteria for evaluation.

  • Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 96 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 96 was analyzed using the missing = failure method.

  • Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    The percentage of participants with HIV-1 RNA < 400 copies/mL at Week 48 was analyzed using the missing = failure method.

  • Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Week 96 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    The percentage of participants with HIV-1 RNA < 400 copies/mL at Week 96 was analyzed using the missing = failure method.

  • Change From Baseline in HIV-1 RNA at Week 48 [ Time Frame: Baseline to Week 48 ] [ Designated as safety issue: No ]
    The change from baseline in log10 HIV-1 RNA (copies/mL) at Week 48 was analyzed.

  • Change From Baseline in HIV-1 RNA at Week 96 [ Time Frame: Baseline to Week 96 ] [ Designated as safety issue: No ]
    The change from baseline in log10 HIV-1 RNA (copies/mL) at Week 96 was analyzed.

  • Change From Baseline in CD4 Cell Count at Week 48 [ Time Frame: Baseline to Week 48 ] [ Designated as safety issue: No ]
    The change from baseline in CD4 cell count (cells/mm^3) at Week 48 was analyzed.

  • Change From Baseline in CD4 Cell Count at Week 96 [ Time Frame: Baseline to Week 96 ] [ Designated as safety issue: No ]
    The change from baseline in CD4 cell count (cells/mm^3) at Week 96 was analyzed.


Enrollment: 724
Study Start Date: July 2008
Estimated Study Completion Date: February 2015
Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Elvitegravir
Participants will be randomized to receive elvitegravir 85 mg or 150 mg once daily, plus placebo to match raltegravir, plus background regimen.
Drug: Elvitegravir
Elvitegravir 85 mg or 150 mg tablet administered orally once daily with food; dose level is dependent on which ritonavir-boosted protease inhibitor (PI/r) is administered as part of the background regimen.
Other Names:
  • Vitekta®
  • GS-9137
Drug: Placebo to match raltegravir
Placebo to match raltegravir administered orally twice daily.
Active Comparator: Raltegravir
Participants will be randomized to receive raltegravir 400 mg twice daily, plus placebo to match elvitegravir, plus background regimen.
Drug: Raltegravir
Raltegravir 400 mg tablet administered orally twice daily according to prescribing information
Other Name: Isentress®
Drug: Placebo to match elvitegravir
Placebo to match elvitegravir administered orally once daily
Drug: Background regimen
Background Regimen is administered according to prescribing information, and contains 1 fully-active ritonavir-boosted protease inhibitor (PI/r) plus 1 or 2 additional agents. The ritonavir-boosted PIs include either atazanavir, darunavir, fosamprenavir, lopinavir (Kaletra®), or tipranavir; the additional agents include abacavir (ABC), Combivir® (lamivudine (LAM)/zidovudine (ZDV) coformulated), didanosine, emtricitabine (FTC), enfuvirtide, Epzicom® (ABC/LAM coformulated), etravirine, LAM, maraviroc, tenofovir disoproxil fumarate (TDF), Truvada®, (FTC/TDF coformulated), and/or ZDV.

Detailed Description:

Due to known drug interactions, participants who are taking ritonavir-boosted atazanavir (ATV/r) or lopinavir/r (LPV/r) as part of their background regimen will receive elvitegravir at a lower dose (85 mg) if randomized to the Elvitegravir Arm.

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00708162

  Show 180 Study Locations
Sponsors and Collaborators
Gilead Sciences
Investigators
Study Director: Javier Szwarcberg, MD, MPH Gilead Sciences
  More Information

Publications:
Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT00708162     History of Changes
Obsolete Identifiers: NCT00707733
Other Study ID Numbers: GS-US-183-0145, EudraCT Number:2007-004225-26
Study First Received: June 30, 2008
Results First Received: October 23, 2014
Last Updated: October 30, 2014
Health Authority: United States: Food and Drug Administration
Australia: Human Research Ethics Committee
Belgium: Federal Agency for Medicinal Products and Health Products
Canada: Health Canada
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Ireland: Irish Medicines Board
Italy: Ministry of Health
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Portugal: National Pharmacy and Medicines Institute
Spain: Spanish Agency of Medicines
Switzerland: Swissmedic
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Gilead Sciences:
HIV
HIV I
Treatment Experienced

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Immune System Diseases
Immunologic Deficiency Syndromes
Lentivirus Infections
RNA Virus Infections
Retroviridae Infections
Sexually Transmitted Diseases
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Virus Diseases

ClinicalTrials.gov processed this record on November 20, 2014