A Study of GSK1349572 Versus Raltegravir (RAL) With Investigator Selected Background Regimen in Antiretroviral-Experienced, Integrase Inhibitor-Naive Adults

Study Overview
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Brief Summary
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ING111762 is a 48 week, randomized, double-blind, active-controlled, multicenter, parallel group, non-inferiority study. The study will be conducted in at least 688 HIV-1 infected antiretroviral experienced, integrase-naïve subjects. Subjects will be randomized 1:1 to receive GSK1349572 50 mg once daily or raltegravir (RAL) 400 mg twice daily, each added to an investigator selected background regimen consisting of at least one fully active agent plus no more than one second single agent which may or may not be active. Antiviral activity, safety, pharmacokinetics (PK), and development of viral resistance will be evaluated.

Detailed Description
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ING111762 is a 48 week, randomized, double-blind, active-controlled, multicenter, parallel group, non-inferiority study. The study will be conducted in at least 688 HIV-1 infected antiretroviral experienced, integrase-naïve subjects. Subjects will be randomized 1:1 to receive GSK1349572 50 mg once daily or raltegravir (RAL) 400 mg twice daily, each added to an investigator selected background regimen consisting of at least one fully active agent plus no more than one second single agent which may or may not be active. Antiviral activity, safety, pharmacokinetics (PK), and development of viral resistance will be evaluated. Subjects must have documented genotypic or phenotypic resistance to at least one member of each of at least two antiretroviral therapy (ART) drug classes [nucleoside/nucleotide reverse transcriptase inhibitor (N[t]RTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitor (PI), fusion inhibitor (T20), or entry inhibitor (chemokine receptor 5 [CCR5] antagonist)]. The primary analysis will take place after the last subject completes 48 weeks on therapy. An additional data cut and analysis will be conducted after the last subject completes 24 weeks on therapy. Subjects randomized to GSK1349572 who successfully complete Week 48 will continue to received GSK1349572 until either it is locally available, until they no longer derive clinical benefit, until they meet a protocol-defined reason for discontinuation, or until development of the compound is terminated. ViiV Healthcare is the sponsor of this study, and GlaxoSmithKline is in the process of updating systems to reflect the change in sponsorship

Official Title
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A Randomized, Double-blind Study of the Safety and Efficacy of GSK1349572 50 mg Once Daily Versus Raltegravir 400 mg Twice Daily, Both Administered With an Investigator-selected Background Regimen Over 48 Weeks in HIV-1 Infected, Integrase Inhibitor-Naïve, Antiretroviral-Experienced Adults

Conditions
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Infection, Human Immunodeficiency Virus, HIV Infections

Intervention / Treatment
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* Drug: GSK1349572
* Drug: Raltegravir
* Drug: GSK1349572 Placebo
* Drug: Raltegravir Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Antiretroviral therapy (ART)-experienced, Human Immunodeficiency Virus (HIV) -1 infected adults at least 18 years of age. Women capable of becoming pregnant must use appropriate contraception during the study (as defined by the protocol). HIV-1 infection as documented by HIV-1 RNA >400 copies/mL (c/mL) at Screening and with at least one consecutive HIV-1 RNA >400 c/mL within the four months prior to Screening (unless the Screening HIV-1 RNA is > 1000 c/mL where no additional plasma HIV-1 RNA assessment is needed). Have documented resistance (via Screening resistance test) to two or more different classes of antiretroviral agents. For subjects off ART for at least one month, if Screening resistance results provide a fully active agent and do not show two class resistance then historical resistance results from the subject's most recent resistance testing may be used, following consultation with the study virologist and /or medical monitor. Integrase inhibitor (INI)-naïve, defined as no prior exposure to any INI (e.g. RAL, elvitegravir, or GSK1349572). Able to provide written informed consent prior to Screening. French subjects: In France, subjects will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category. Exclusion Criteria: Screening resistance test result indicates no fully active antiviral agents are available for design of the background regimen. Subject-virus does not yield results using genotype/phenotype/tropism at Screening (assay data is essential for eligibility determination). Women who are breastfeeding. Any evidence of an active AIDS-defining condition (except cutaneous Kaposi's sarcoma not requiring systemic therapy or CD4+ <200c/mm3). Subjects with moderate to severe hepatic impairment as defined by Child-Pugh classification. Recent history (less than or equal to 3 months) of upper or lower gastrointestinal bleed, with the exception of anal or rectal bleeding. Anticipated need for hepatitis C therapy during the study. History or presence of allergy or intolerance to the study drugs or their components or drugs of their class. History of malignancy within the past 5 years or ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma; other localized malignancies require agreement between the investigator and study medical monitor for inclusion of the subject. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days prior to Screening. Treatment with any of the following agents within 28 days of Screening: radiation therapy, cytotoxic chemotherapeutic agents, any immunomodulator. Treatment with any agent, other than licensed ART, which has documented activity against HIV-1 in vitro within 28 days of first dose of investigational product. Exposure to an experimental drug and/or experimental vaccine within either 28 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the experimental test agent - whichever is longer, prior to the first dose of IP. French subjects recruited at sites in France will be excluded if the subject has participated in any study using an investigational drug and/or vaccine within 60 days or 5 half-lives, or twice the duration of the biological effect of the experimental drug or vaccine - whichever is longer - prior to screening for the study or the subject plans to participate simultaneously in another clinical study. Any acute or verified Grade 4 laboratory abnormality. Alanine aminotransferase (ALT) >5 times the upper limit of normal (ULN). ALT greater than or equal to 3xULN and bilirubin greater than or equal to 1.5xULN (with >35% direct bilirubin).

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK1349572 + Raltegravir Placebo<br>Subjects will receive GSK1349572 50mg once daily plus raltegravir placebo twice daily. | Drug: GSK1349572<br>* 50mg once daily<br>Drug: Raltegravir Placebo<br>* Inactive placebo tablet twice daily<br>|
| Active Comparator: Raltegravir + GSK1349572 Placebo<br>Subjects will receive raltegravir 400mg twice daily plus GSK1349572 placebo once daily. | Drug: Raltegravir<br>* 400mg twice daily<br>Drug: GSK1349572 Placebo<br>* Inactive placebo tablet once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With HIV-1 Ribonucleic Acid (RNA) <50 Copies/Milliliter (c/mL) at Week 48 | The percentage of participants with Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) <50 c/mL at Week 48 was assessed using the Missing, Switch or Discontinuation = Failure (MSDF), as codified by the Food and Drug Administration (FDA) snapshot algorithm. This algorithm treated all participants without HIV-1 RNA at Week 48 as nonresponders, as well as participants who switched their concomitant ART prior to Week 48 as follows: background ART substitutions non-permitted per protocol (one background ART substitution was permitted for safety or tolerability); background ART substitutions permitted per protocol unless the decision to switch was documented as being before or at the first on-treatment visit where HIV-1 RNA was assessed. Otherwise, virologic success or failure was determined by the last available HIV-1 RNA assessment while the participant was on-treatment in the randomized phase of the study. | At Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants (Par.) With Detectable Virus That Has Genotypic or Phenotypic Evidence of Treatment-emergent Integrase Inhibitor (INI) Resistance at Time of Protocol Defined Virology Failure (PDVF) | For par. meeting one of the criteria for PDVF, plasma samples collected at the time point of virologic failure and Baseline were tested to evaluate any potential genotypic and/or phenotypic evolution of resistance. PDVF was defined as (A) virologic non-response: a decrease in plasma HIV-1 RNA of <1 logarithm to base 10 (log10) copies/mL by Week 16, with subsequent confirmation, unless plasma HIV-1 RNA is <400 copies/ mL; confirmed plasma HIV-1 RNA levels >=400 copies/mL on or after Week 24 or (B) virologic rebound: confirmed rebound in plasma HIV-1 RNA levels to >=400 copies/mL after prior confirmed suppression to <400 copies/mL; confirmed plasma HIV-1 RNA levels >1 log10 copies/mL above the nadir value, where nadir is >=400 copies/mL.Treatment-emergent IN mutations are those detected at the time of PDVF but not at Baseline. | Baseline (Day 1) until PDVF (Up to Week 48) | 
| Number of Participants With Plasma HIV-1 RNA <50 c/mL at Week 24 | The number of participants with Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) <50 c/mL at Week 24 was assessed using the Missing, Switch or Discontinuation = Failure (MSDF), as codified by the Food and Drug Administration (FDA) snapshot algorithm. This algorithm treated all participants without HIV-1 RNA at Week 24 as nonresponders, as well as participants who switched their concomitant ART prior to Week 24 as follows: background ART substitutions non-permitted per protocol (one background ART substitution was permitted for safety or tolerability); background ART substitutions permitted per protocol unless the decision to switch was documented as being before or at the first on-treatment visit where HIV-1 RNA was assessed. Otherwise, virologic success or failure was determined by the last available HIV-1 RNA measurement through Week 24 (within window) while the participant was on-treatment. The result below corresponds to the Week 24 interim analysis. | At Week 24 | 
| Number of Participants With Plasma HIV-1 RNA <400 c/mL at Week 24 and Week 48 | The number of participants with Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) <400 c/mL at the visit of interest was assessed using the Missing, Switch or Discontinuation = Failure (MSDF), as codified by the Food and Drug Administration (FDA) snapshot algorithm. This algorithm treated all participants without HIV-1 RNA at the visit of interest as nonresponders, as well as participants who switched their concomitant ART prior to the visit of interest as follows: background ART substitutions non-permitted per protocol (one background ART substitution was permitted for safety or tolerability); background ART substitutions permitted per protocol unless the decision to switch was documented as being before or at the first on-treatment visit where HIV-1 RNA was assessed. Otherwise, virologic success or failure was determined by the last available HIV-1 RNA measurment (within window) for the timepoint of interest while the participant was on-treatment. | At Week 24 and Week 48 | 
| Absolute Values of Cluster of Differentiation 4+ (CD4+) Cell Counts at Baseline (Day 1) and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 96 and 144 | Blood samples were collected at specified time points to assess CD4+ using flow cytometry. Median and interquartile range are presented. Baseline was the latest pre-dose assessment value (Day 1). | Baseline (Day 1) and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 96 and 144 | 
| Change From Baseline in CD4+ Cell Counts at Weeks 4, 8, 12,16, 24, 32, 40, 48, 96 and 144 | Blood samples were collected at specified time points to assess CD4+. It was evaluated by flow cytometry. Baseline was the latest pre-dose assessment value (Day 1). Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Median and interquartile range is presented. | Baseline (Day 1) and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 96 and 144 | 
| Number of Participants With Post-Baseline HIV-associated Conditions, Excluding Recurrences, and Disease Progressions | Clinical disease progression (CDP) was assessed according to the Centers for Disease Control and Prevention (CDC) HIV-1 classification system. Category (CAT) A: one or more of following conditions (CON), without any CON listed in Categories B and C: Asymptomatic HIV infection, persistent generalized lymphadenopathy, acute (primary) HIV infection with accompanying illness or history of acute HIV infection. CAT B: Symptomatic CON that are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or that are considered by physicians to have clinical course or to require management that is complicated by HIV infection; and not included among CON listed in clinical CAT C. CAT C:Clinical CON listed in acquired immunodeficiency syndrome (AIDS) surveillance case definition. Indicators of CDP defined as:CDC CAT A at Baseline (BS) to CDC CAT C event (EV); CDC CAT B at BS to CDC CAT C EV; CDC CAT C at BS to new CDC CAT C EV; or CDC CAT A, B, or C at BS to death. | Up to Week 480 | 
| Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities | All Grade 1 to 4 post-Baseline-emergent chemistry toxicities included alanine aminotransferase (ALT), albumin, alkaline phosphatase (ALP), asparate aminotransferase (AST), carbon dioxide (CO2) content/bicarbonate, cholesterol, creatine kinase (CK), creatinine, hyperglycemia, hyperkalemia, hypernatremia, hypoglycemia, hypokalemia, hyponatremia, low density lipoprotein (LDL) cholesterol calculation, lipase, total bilirubin, and triglycerides. All Grade 1 to 4 post-Baseline-emergent hematology toxities included hemoglobin, platelet count, total neutrophils, and white blood cell count. The Division of AIDS (DAIDS) defined toxicity grades as follows: Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, potentially life threatening; Grade 5, death. Higher the grade, more severe the symptoms. | From Baseline (Day 1) until Week 48, including participants with post-treatment events occurring after Week 48 for participants not entering the post-Week 48 Open-Label phase of the study | 
| Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities | Blood samples were collected for the analysis of clinical chemistry and hematology parameters: Alanine aminotransferase (ALT), albumin, alkaline phosphate (ALP), aspartate aminotransferase (AST), carbon dioxide (CO2) content/bicarbonate, cholesterol, creatine kinase (CK), creatinine, hyperglycemia, hyperkalemia, hypernatremia, hypoglycemia, hypokalemia, hypoonatremia, LDL cholesterol, lipase, total bilirubin, triglycerides, hemoglibin, neutrophils, platelets, white blood cells. Any abnormality in clinical chemistry and hematology parameters were evaluated according to the DAIDS toxicity scale From Grade 1 to 4: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) and Grade 4 (Potentially life-threatening).Higher the grade, more severe the symptoms. | From Week 48 to Week 480 | 
| DTG PK Parameters Including Maximum Plasma Drug Concentration (Cmax), Minimal Plasma Drug Concentration (Cmin), and Average Plasma Pre-dose Concentration (C0_avg) | Cmax, Cmin and C0_avg were assessed by population pharmacokinetic (PK) modeling using sparse PK samples which were collected as follows: one pre-dose sample and one post-dose sample at 1 to 3 hours/4 to 12 hours at Week 4, one pre-dose sample at Week 24, and one pre-dose sample and one post-dose sample at 1 to 3 hours/4 to 12 hours at Week 48. Cmax, Cmin and C0_avg were estimated and reported here. | Pre-dose and at 1 to 3 hours or 4 to 12 hours post-dose at Week 4; Pre-dose at Week 24; Pre-dose and 1 to 3 hours or 4 to 12 hours post-dose at Week 48 | 
| DTG PK Parameter Including Pre-dose Concentration (C0) | C0 was assessed by population PK modeling using sparse PK samples which were collected as follows: one pre-dose sample and one post-dose sample at 1 to 3 hours/4 to 12 hours at Week 4, one pre-dose sample at Week 24, and one pre-dose sample and one post-dose sample at 1 to 3 hours/4 to 12 hours at Week 48. DTG predose concentration (C0) at Week 4, Week 24, and Week 48 was estimated and reported here. | Pre-dose at Weeks 4, 24 and 48 | 
| DTG PK Parameters Including Area Under the Plasma Concentration-time Curve From Time Zero to Time Tau Over a Dosing Interval at Steady State (AUC[0-tau]) | AUC is defined as the area under the DTG concentration-time curve as a measure of drug exposure over time. AUC(0-tau) is defined as the area under the plasma concentration-time curve from time zero to time tau over a dosing interval at steady state, where tau is the length of the dosing interval of DTG. AUC was assessed by population pharmacokinetic (PK) modeling using sparse PK samples which were collected as follows: one pre-dose sample and one post-dose sample at 1 to 3 hours/4 to 12 hours at Week 4, one pre-dose sample at Week 24, and one pre-dose sample and one post-dose sample at 1 to 3 hours/4 to 12 hours at Week 48. | Pre-dose and at 1 to 3 hours or 4 to 12 hours post-dose at Week 4; Pre-dose at Week 24; Pre-dose and 1 to 3 hours or 4 to 12 hours post-dose at Week 48 | 
| Change From Baseline in European Quality of Life-5 Dimensions-3 Levels (EQ-5D-3L) Utility Score | The EQ-5D-3L questionnaire provides a profile of participant function and a global health state rating. The five-item measure has one question assessing each of five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression and 3 levels for each dimension including 1=no problems, 2=some problems, 3=extreme problems. The health state is defined by combining the levels of answers from each of the 5 questions. Each health state is referred to in terms of a 5 digit code. Health state 5 digit code is translated into utility score, which is valued up to 1 (perfect health) with lower values meaning worse state. EQ-5D-3L utility score ranges from -0.594 to 1. Higher scores indicate better health. Baseline was the latest pre-dose assessment value (Day 1) and change from Baseline=post-dose value minus Baseline value. | Baseline (Day 1) and at Weeks 24 and 48 | 
| Change From Baseline in European Quality of Life-5 Dimensions-3 Levels (EQ-5D-3L) Thermometer Scores | The EQ-5D-3L questionnaire provides a profile of participant function and a global health state rating. The five-item measure has one question assessing each of five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression and 3 levels for each dimension including 1=no problems, 2=some problems, 3=extreme problems. EQ-5D-3L included EQ visual Analogue scale (EQ VAS) 'Thermometer' which provided Self-rated current health status. Participants were asked to rate their current health status using the visual analogue scale 'Thermometer'. Score ranged from 0 (worst imaginable health state) to 100 (best imaginable health state). Higher scores indicate better heath. Baseline was the latest pre-dose assessment value (Day 1) and change from Baseline=post-dose value minus Baseline value. | Baseline (Day 1) and at Weeks 24 and 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ART-experienced, Integrase inhibitor, Raltegravir, GSK1349572, Integrase inhibitor naive