Multicenter, Randomized, Double-Blind, Double-Dummy, Phase 3 Study of the Safety and Efficacy of Ritonavir-Boosted Elvitegravir (EVG/r) Versus Raltegravir (RAL)

• To evaluate the efficacy, safety and tolerability of the two treatment arms through 96 weeks of treatment. [ Time Frame: 96 weeks ] [ Designated as safety issue: No ]
• To evaluate the long-term safety, tolerability, and efficacy of elvitegravir administered with a background regimen [ Time Frame: Open Label Extension ] [ Designated as safety issue: No ]

The purpose of this study is to compare the safety, tolerability and efficacy of a regimen containing once-daily ritonavir-boosted elvitegravir or twice-daily raltegravir added to a background regimen 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.

This is a double-blind, double-dummy, multicenter, randomized, active-controlled 96-week study to assess the safety and efficacy of a regimen containing ritonavir-boosted elvitegravir versus raltegravir, each administered with a background regimen (BR) containing a fully-active ritonavir-boosted protease inhibitor (PI) and a second single agent in HIV-1 infected, antiretroviral treatment-experienced adults. Subjects will be randomized in a 1:1 ratio to one of the following two treatment arms:

• Treatment Arm 1: Ritonavir-boosted elvitegravir 150 mg QD (ritonavir-boosted elvitegravir 85 mg QD for subjects taking atazanavir/r or lopinavir/r as part of their BR) + BR (N = 350)
• Treatment Arm 2: Raltegravir 400 mg BID + BR (N = 350)

Due to known pharmacokinetic interactions, subjects who are taking atazanavir/r (ATV/r) or lopinavir/r (LPV/r) as part of their BR will receive elvitegravir 85 mg if randomized to Treatment Arm 1.

The BR shall be constructed by the investigator based on viral resistance testing and shall be composed of a fully-active ritonavir-boosted PI and a second single agent.

The fully-active PI is defined by phenotypic resistance analysis. For phenotypic susceptibility, fully active is defined as being below the lower clinical or biological cutoff. The following ritonavir-boosted PIs are allowed to be prescribed by the investigator as part of the BR: atazanavir/r, darunavir/r, fosamprenavir/r, lopinavir/r, or tipranavir/r. Subjects must 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 elvitegravir. No other marketed PIs will be allowed as part of the BR due to unknown pharmacokinetic interactions.

The second single agent may or may not be fully-active and can be one nucleoside or nucleotide reverse transcriptase inhibitor (NRTI), etravirine, maraviroc, or T-20. However, the second single agent must not include an integrase inhibitor; the non-nucleoside reverse transcriptase inhibitors (NNRTI) efavirenz, nevirapine, or delavirdine (due to unknown pharmacokinetic interactions); or fixed-dose combination antiretroviral therapies.

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

• Drug: elvitegravir
  Elvitegravir 85 mg, 150 mg tablets or matching placebo administered orally QD (with ritonavir-boosted PI) to be taken with food.
• Drug: Raltegravir
  Raltegravir 400 mg tablets or matching placebo administered orally BID and to be taken according to the prescribing information.
  Other Name: Isentress

• Experimental: 1
  Ritonavir-boosted elvitegravir 150 mg QD (ritonavir-boosted elvitegravir 85 mg QD for subjects taking atazanavir/r or lopinavir/r as part of their BR) + BR (N = 350)
  Intervention: Drug: elvitegravir
• Active Comparator: 2
  Raltegravir 400 mg BID + BR (N = 350)
  Intervention: Drug: Raltegravir

Inclusion Criteria:

• Plasma HIV-1 RNA levels greater than or equal to 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 and must remain on screening regimen until the baseline visit
• Eligible to receive one of the fully-active ritonavir-boosted-PIs, and an allowed second agent
• Normal ECG
• Adequate renal function
• Hepatic transaminases less than or equal to 2.5 x upper limit of normal
• Total bilirubin less than or equal to 1.5 mg/dL, or normal direct bilirubin
• Adequate hematologic function
• Prothrombin Time less than or equal to 1.25 x ULN
• Serum amylase less than 1.5 x ULN
• Negative serum pregnancy test (females of childbearing potential only)
• Males and females of childbearing potential must agree to use highly effective contraception methods
• Age greater than or equal to 18 years
• Life expectancy greater than or equal to 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
• Subjects experiencing ascites
• Subjects experiencing encephalopathy
• Females who are breastfeeding
• Positive serum pregnancy test at any time during the study (female of childbearing potential)
• Subjects 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 therapy
• Participation in any other clinical trial (except for the etravirine expanded access program), without prior approval from sponsor
• Any other clinical condition or prior therapy that would make subjects unsuitable for the study
• Known hypersensitivity to study drug, metabolites or formulation excipients