A Trial Comparing GSK1349572 50mg Once Daily to Raltegravir 400mg Twice Daily

Study Overview
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Brief Summary
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The purpose of this trial is to assess the non-inferior antiviral activity of GSK1349572 50 mg once daily versus RAL 400mg twice daily over 48 weeks; non-inferiority will also be tested at Week 96. Both GSK1349572 and RAL will be given in combination with fixed-dose dual NRTI therapy (ABC/3TC or TDF/FTC). This study will be conducted in HIV-1 infected ART-naïve adult subjects.

Detailed Description
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ING113086 is a Phase 3 randomized, double-blind, double dummy, active-controlled, multicenter, study conducted in approximately 788 HIV-1 infected ART-naïve subjects. Subjects will be randomized 1:1 one of the following treatment arms: GSK1349572 50 mg once daily (approximately 394 subjects) + fixed-dose dual NRTI therapy (either ABC/3TC or TDF/FTC) OR 400 mg RAL twice daily (approximately 394 subjects) + fixed-dose dual NRTI therapy (either ABC/3TC or TDF/FTC) Analyses will be conducted at 48 weeks and 96 weeks. Subjects randomized to receive GSK1349572 and who successfully complete 96 weeks of treatment will continue to have access to GSK1349572 through the study until either it is locally available, as long as they continue to derive clinical benefit. ViiV Healthcare is the new 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 50mg Once Daily to Raltegravir 400mg Twice Daily Both Administered With Fixed-dose Dual Nucleoside Reverse Transcriptase Inhibitor Therapy Over 96 Weeks in HIV-1 Infected Antiretroviral Therapy Naive Adult Subjects

Conditions
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Infection, Human Immunodeficiency Virus I

Intervention / Treatment
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* Drug: GSK1349572 (dolutegravir)
* Drug: raltegravir
* Other: GSK1349572 Placebo
* Other: ABC/3TC
* Other: TDF/FTC
* Other: raltegravir Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Screening plasma HIV-1 RNA ≥1000 c/mL Antiretroviral-naïve (≤ 10 days of prior therapy with any antiretroviral agent following a diagnosis of HIV-1 infection) Ability to understand and sign a written informed consent form Willingness to use approved methods of contraception to avoid pregnancy (women of child bearing potential only) Age equal to or greater than 18 years Exclusion Criteria: Women who are pregnant or breastfeeding; Active Center for Disease and Prevention Control (CDC) Category C disease Moderate to severe hepatic impairment Anticipated need for HCV therapy during the study Allergy or intolerance to the study drugs or their components or drugs of their class Malignancy within the past 5 years Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening Treatment with radiation therapy, cytotoxic chemotherapeutic agents or any immunomodulator within 28 days of Screening Exposure to an agent with documented activity against HIV-1 in vitro or an experimental vaccine or drug within 28 days of first dose of study medication Primary viral resistance in the Screening result Verified Grade 4 laboratory abnormality ALT >5 xULN ALT ≥ 3xULN and bilirubin ≥ 1.5xULN (with >35% direct bilirubin); Estimated creatinine clearance <50 mL/min Recent history (≤3 months) of upper or lower gastrointestinal bleed

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 (N= 394)<br>GSK1349572 50mg once daily + raltegravir placebo twice daily + NRTI background therapy once daily | Drug: GSK1349572 (dolutegravir)<br>* GSK1349572 50 mg taken once daily with or without food<br>Other: GSK1349572 Placebo<br>* GSK1349572 placebo taken once daily<br>Other: ABC/3TC<br>* Abacavir/Lamivudine background therapy once daily<br>Other: TDF/FTC<br>* Tenofovir/emtricitabine background therapy once daily<br>|
| Active Comparator: raltegravir (N= 394)<br>raltegravir 400mg twice daily + GSK1349572 placebo once daily + NRTI background therapy once daily | Drug: raltegravir<br>* raltegravir 400mg taken twice daily<br>Other: ABC/3TC<br>* Abacavir/Lamivudine background therapy once daily<br>Other: TDF/FTC<br>* Tenofovir/emtricitabine background therapy once daily<br>Other: raltegravir Placebo<br>* raltegravir placebo taken twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) [HIV-1RNA] <50 Copies (c)/Milliliter (mL) Through Week 48 | Percentage of participants with plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) with <50 c/mL was assessed using the Missing, Switch or Discontinuation = Failure (MSDF), as codified by the Food and Drug Administration (FDA) snapshot algorithm. The algorithm treats all participants without HIV-1 RNA data as non-responders, as well as participants who switch their concomitant Antiretroviral Therapy (ART) prior to Week 48 as follows: background ART substitutions not permitted per study; background ART substitutions permitted per study 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 will be determined by the last available HIV-1 RNA assessment while the subject was on-treatment. Intent-to-Treat Exposed (ITT-E) Population comprised all randomized participants who received at least one dose of study medication. | Baseline up to Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Detectable HIV-1 Virus That Has Genotypic or Phenotypic Evidence of INI Resistance. | Number of participants with detectable virus that has genotypic or phenotypic evidence of Integrase Inhibitor (INI) resistance were assessed at Week 48 and Week 96. Integrase inhibitors are a class of antiretroviral drug designed to block the action of integrase, a viral enzyme that inserts the viral genome into the deoxyribonucleic acid (DNA) of the host cell. | Week 48 and Week 96 | 
| Number of Participants With Plasma HIV-1 RNA <50 c/mL | The number of participants with plasma HIV-1 RNA level <50 c/mL was assessed at Week 96. | Week 96 | 
| Number of Participants With Plasma HIV-1 RNA <400 c/mL | The number of participants with plasma HIV-1 RNA level <400 c/mL was assessed at Week 48 and Week 96. | Week 48 and Week 96 | 
| Change From Baseline in Plasma HIV-1 RNA Over Time | Change from Baseline in plasma HIV-1 RNA over time was assessed at Baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96. Baseline was defined as the measurements performed on Day 1. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants with data available at the specified time points were analyzed (represented by n=x,x in the category titles). | Baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96 | 
| Absolute Values in Plasma HIV-1 RNA Over Time | Absolute values in plasma HIV-1 RNA over time was assessed at Baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96. Only those participants with data available at the specified time points were analyzed (represented by n=x,x in the category titles). | Baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96 | 
| Change From Baseline in Cluster of Differentiation (CD)4+ Cell Counts Over Time | CD4 lymphocyte cells (also called T-cells or T-helper cells) are the primary targets of HIV. The CD4 count and the CD4 percentage mark the degree of immuno compromise. The CD4 count is used to stage the participants disease, determine the risk of opportunistic illnesses, assess prognosis, and guide decisions about when to start ART. Changes from Baseline in CD4+ cell counts over time was assessed at Baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96. Baseline was defined as measurements performed on Day 1. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants with data available at the specified time points were analyzed (represented by n=x,x in the category titles). | Baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96 | 
| Absolute Values in CD4+ Cell Counts Over Time | CD4 lymphocyte cells (also called T-cells or T-helper cells) are the primary targets of HIV. The CD4 count and the CD4 percentage mark the degree of immuno compromise. The CD4 count is used to stage the patient's disease, determine the risk of opportunistic illnesses, assess prognosis, and guide decisions about when to start antiretroviral therapy absolute values in CD4+ cell counts over time was assessed at Baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96. Only those participants with data available at the specified time points were analyzed (represented by n=x,x in the category titles). | Baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96 | 
| Number of Participants With the Indicated Post-Baseline HIV-associated Conditions and Progression, Excluding Recurrences | 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 the 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 a clinical course or to require management that is complicated by HIV infection; and not included among CON listed in clinical CAT C. CAT C: the clinical CON listed in the AIDS surveillance case definition. Indicators of CDP were defined as: CDC CAT A at Baseline to a CDC CAT C event (EV); CDC CAT B at Baseline to a CDC CAT C EV; CDC CAT C at Baseline to a new CDC CAT C EV; or CDC CAT A, B, or C at Baseline to death. | From Baseline until Week 96 | 
| Number of Participants With the Indicated Grade 1 to 4 Clinical Chemistry and Hematology Toxicities/Laboratory Adverse Events (AEs) | All Grade 1 to 4 post-Baseline-emergent chemistry toxicities included alanine aminotransferase (ALT), 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, phosphorus inorganic, 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. Safety Population: all participants who received at least one dose of investigational product | From Baseline until Week 96 | 
| Area Under the Plasma Concentration-time Curve From Time Zero to Time Tau [AUC(0-tau)] of DTG | 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. The predicted individual AUC(0-tau) were obtained from the final population PK model by an empirical Bayes estimation. Blood samples for PK assessments were collected at pre-dose (within 15 minutes prior to dose) at Week 4, Week 24, and Week 48 and 1 to 3 hours post-dose or 4 to 12 hours post-dose at Week 4 and Week 24. If 1 to 3 hours post-dose was completed at Week 4, then the 4 to12 hour post-dose must be obtained at Week 48, and vice versa. The Pharmacokinetic (PK) Concentration Population comprised of all participants who received DTG, had undergone PK sampling during the study, and provided evaluable DTG plasma concentration data. | Week 4, Week 24, and Week 48 | 
| Maximum Plasma Concentration (Cmax) and Concentration at the End of a Dosing Interval (Ctau) of DTG | The maximum plasma concentration (Cmax) and concentration at the end of a dosing interval (Ctau) of DTG were assessed at Week 48. The predicted individual Cmax and Ctau were obtained from the final population PK model by simulation of the concentration-time profiles. Blood samples for PK assessments were collected at pre-dose (within 15 minutes prior to dose) at Week 4, Week 24, and Week 48 and 1 to 3 hours post-dose or 4 to 12 hours post-dose at Week 4 and Week 24. If 1 to 3 hour post-dose was completed at Week 4, then the 4 to12 hour post-dose must be obtained at Week 48, and vice versa. | Week 4, Week 24, and Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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integrase inhibitor, HIV Infection, raltegravir, GSK1349572