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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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HIV Infection

Intervention / Treatment
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* Drug: Elvitegravir
* Drug: Raltegravir
* Drug: EVG placebo
* Drug: RAL placebo
* Drug: Background regimen


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Elvitegravir<br>EVG 85 mg or 150 mg + RAL placebo + background regimen in the Randomized Phase, followed by EVG 85 mg or 150 mg + background regimen in the Open-Label Phase. Participants receiving lopinavir/ritonavir (LPV/r) or atazanavir/ritonavir (ATV/r) as part of their background regimen will receive EVG 85 mg; all other participants will receive EVG 150 mg. | Drug: Elvitegravir<br>* Elvitegravir (EVG) tablet administered orally once daily with food<br>* Other names: GS-9137;Drug: RAL placebo<br>* RAL placebo administered orally twice daily.<br>Drug: Background regimen<br>* Background Regimen (administered according to prescribing information) contains 1 fully-active ritonavir-boosted protease inhibitor (PI/r) plus 1 or 2 additional agents. The ritonavir-boosted PIs include either ATV, darunavir, fosamprenavir, LPV (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.<br>|
| Active Comparator: Raltegravir<br>RAL 800 mg (400 mg twice daily) + EVG placebo + background regimen in the Randomized Phase, followed by EVG 85 mg or 150 mg + background regimen in the Open-Label Phase. Participants receiving LPV/r or ATV/r as part of their background regimen in the Open-Label Phase will receive EVG 85 mg; all other participants will receive EVG 150 mg. | Drug: Raltegravir<br>* Raltegravir tablet administered orally twice daily according to prescribing information<br>* Other names: Isentress®;Drug: EVG placebo<br>* Placebo to match elvitegravir administered orally once daily<br>Drug: Background regimen<br>* Background Regimen (administered according to prescribing information) contains 1 fully-active ritonavir-boosted protease inhibitor (PI/r) plus 1 or 2 additional agents. The ritonavir-boosted PIs include either ATV, darunavir, fosamprenavir, LPV (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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 50 Copies/mL at Week 48 | 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. | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 50 Copies/mL at Week 96 | 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. | Week 96 | 
| Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 400 Copies/mL at Week 48 | 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. | Week 48 | 
| Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 400 Copies/mL at Week 96 | 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. | Week 96 | 
| Virologic Response at Week 48 (HIV-1 RNA < 50 Copies/mL) | Virologic response at Week 48 (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 the viral load along with study drug discontinuation status at the predefined time point within an allowed window of time. | Week 48 | 
| Virologic Response at Week 96 (HIV-1 RNA < 50 Copies/mL) | 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 the viral load along with study drug discontinuation status at the predefined time point within an allowed window of time. | Week 96 | 
| Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 50 Copies/mL) up to Week 48 | 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. | Baseline to Week 48 | 
| Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 50 Copies/mL) up to Week 96 | 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. | Baseline to Week 96 | 
| Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 400 Copies/mL) up to Week 48 | 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. | Baseline to Week 48 | 
| Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 400 Copies/mL) up to Week 96 | 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. | Baseline to Week 96 | 
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 | 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. | Week 48 | 
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 96 | The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 96 was analyzed using the missing = failure method. | Week 96 | 
| Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Week 48 | The percentage of participants with HIV-1 RNA < 400 copies/mL at Week 48 was analyzed using the missing = failure method. | Week 48 | 
| Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Week 96 | The percentage of participants with HIV-1 RNA < 400 copies/mL at Week 96 was analyzed using the missing = failure method. | Week 96 | 
| Change From Baseline in HIV-1 RNA at Week 48 | The change from baseline in log10 HIV-1 RNA (copies/mL) at Week 48 was analyzed. | Baseline to Week 48 | 
| Change From Baseline in HIV-1 RNA at Week 96 | The change from baseline in log10 HIV-1 RNA (copies/mL) at Week 96 was analyzed. | Baseline to Week 96 | 
| Change From Baseline in CD4 Cell Count at Week 48 | The change from baseline in CD4 cell count (cells/mm^3) at Week 48 was analyzed. | Baseline to Week 48 | 
| Change From Baseline in CD4 Cell Count at Week 96 | The change from baseline in CD4 cell count (cells/mm^3) at Week 96 was analyzed. | Baseline to Week 96 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, HIV I, Treatment Experienced