Dose-finding Study of GSK2248761 in Antiretroviral Therapy-Naive Subjects (SIGNET)

• HIV-1 viral load [ Time Frame: Week 16 ] [ Designated as safety issue: No ]
• Incidence of AEs [ Time Frame: Week 16 ] [ Designated as safety issue: Yes ]
• Incidence of SAEs [ Time Frame: Week 16 ] [ Designated as safety issue: Yes ]

• Incidence of HIV Associated Conditions [ Time Frame: through Week 96 ] [ Designated as safety issue: Yes ]
• Changes in Immunologic Function (CD4/CD8 cell counts) [ Time Frame: through Week 96 ] [ Designated as safety issue: No ]
• Changes in Viral Genotype [ Time Frame: through Week 96 ] [ Designated as safety issue: No ]
• Absolute Values and Changes Over Time in Laboratory Parameters [ Time Frame: through Week 96 ] [ Designated as safety issue: Yes ]
• Study Discontinuation Due to Adverse Events [ Time Frame: through Week 96 ] [ Designated as safety issue: Yes ]
• Changes in ECG [ Time Frame: through Week 96 ] [ Designated as safety issue: Yes ]
• Plasma GSK2248761 PK parameters - Cmin [ Time Frame: through Week 24 ] [ Designated as safety issue: No ]
• Effect of Plasma GSK2248761 Concentrations on Plasma HIV-1 RNA levels [ Time Frame: through Week 24 ] [ Designated as safety issue: No ]
• Incidence of AEs [ Time Frame: through Week 96 ] [ Designated as safety issue: Yes ]
• Incidence of SAEs [ Time Frame: through Week 96 ] [ Designated as safety issue: Yes ]
• Plasma GSK2248761 PK parameters - Cmax [ Time Frame: through Week 24 ] [ Designated as safety issue: No ]
• Effect of Plasma GSK228761 Concentrations on Adverse Events [ Time Frame: through Week 24 ] [ Designated as safety issue: Yes ]
• Changes in Viral Phenotype [ Time Frame: through Week 96 ] [ Designated as safety issue: No ]

This 96 week, Phase 2b study in 150 HIV-1 infected antiretroviral (ART) naive adult subjects consists of a dose-ranging evaluation of GSK2248761 at blinded doses of 100 mg and 200 mg once daily with a control arm of open-label efavirenz (EFV) 600 mg once daily. The background ART for all 3 arms will be chosen by the Investigators and will be either abacavir/lamivudine [ABC/3TC] or tenofovir/emtricitabine [TDF/FTC] fixed dose combination (FDC) tablets. Antiviral activity, safety, PK, and development of viral resistance will be evaluated.

Study SGN113404 is a phase 2b randomized, partially blinded, multicenter, parallel group, dose-ranging study. The study will be conducted in approximately 150 HIV-1 infected ART naïve subjects. The background NRTIs to be co-administered with GSK2248761 or EFV will be selected by Investigators prior to randomization and will be either abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) fixed dose combination (FDC) tablets.

Subjects will participate in a Screening period (Day -28 to Day -1). Subjects may be re-screened once. Subjects will be randomized 1:1:1 to receive 100 mg of GSK2248761 once daily (50 subjects), 200 mg of GSK2248761 once daily (50 subjects) or 600 mg of EFV once daily (50 subjects). All three arms will be combined with either 300 mg/200 mg TDF/FTC or 600 mg/300 mg ABC/3TC, as chosen by the Investigator. The Investigators and subjects will be blinded to the dose of GSK2248761 being administered but will know whether they receive EFV or GSK2248761. The randomization will be stratified by HIV-1 viral load (VL) at screening, < 100,000 copies/mL or >/ 100,000 copies/mL as well as the choice of backbone NRTI, TDF/FTC or ABC/3TC.

This study will be enrolled in two stages. The first stage of the study will enroll approximately 30 subjects, at which time enrollment will be paused. An analysis of safety and tolerability will be reviewed by a safety review committee (SRC) once all subjects enrolled in Stage 1 reach Week 4. The SRC review will determine if the safety and tolerability profile of GSK2248761 supports the continuation of the trial and enrollment of an additional 120 subjects. All subjects will continue on study medications during this Week 4 analysis.

Additional analyses will be conducted once all subjects complete Week 4, Week 16, Week 24 and Week 48. A second review of the safety and tolerability of GSK2248761 will be performed by the SRC once all subjects reach Week 4. There will not be a pause in the study during the Week 4 analysis of all subjects.

The Week 16 and Week 24 analyses will be used respectively to select and confirm the optimal dose of GSK2248761 for continuation. This dose will be selected based on a statistical analysis of antiviral activity, safety and tolerability criteria. If, after confirmation of the optimal dose of GSK2248761 by the Week 24 analysis, both doses are considered acceptable based on efficacy, safety and PK data, then both arms will be continued through Week 48.

Beyond Week 48, those subjects who were randomized to the non-selected dose of GSK2248761 and have not met any criteria for discontinuation will be given the option to switch to the selected dose of GSK2248761 or to discontinue permanently from the study. Once they have switched to the selected dose they will be in the Open-Label phase of the study through Week 96. After Week 96, subjects receiving GSK2248761 will be given the option to continue to receive GSK2248761 until it is locally approved and commercially available, as long as they continue to derive clinical benefit without a protocol-defined reason for discontinuation.

Subjects randomized to EFV will have the option to continue to receive EFV through Week 96 unless they meet a protocol-defined reason for discontinuation. All subjects will have the option to continue TDF/FTC or ABC/3TC through Week 96. After Week 96, subjects will be expected to obtain local access to all commercially available ART.

Randomization will be stratified by:

• HIV-1 RNA < or >/ 100,000 copies/mL at screening
• Use of ABC/3TC or TDF/FTC FDC tablets as initial background ART

Switch of a background NRTI for toxicity management to an alternative marketed NRTI is allowed once. Switches of a background NRTI for any other reason are not permitted in the study. A switch of GSK2248761 or EFV is not allowed.

Study Endpoints /Assessments: Subjects will have assessments performed which will include baseline demographics, disease characteristics, and safety (laboratory and clinical evaluations). On study safety, efficacy, virologic, immunologic, and PK evaluations will be conducted.

Primary Endpoint: The proportion of subjects with HIV-1 RNA <50copies/mL at Week 16. Dose selection will be based primarily on antiviral activity and tolerability in conjunction with immunologic, safety, virologic resistance and PK measures. Data from the Week 24 analysis will be used to confirm dose selection.

ViiV Healthcare is the new sponsor of this study, and GlaxoSmithKline is in the process of updating systems to reflect the change in sponsorship

• Drug: GSK2248761 100 mg once daily
  1x100 mg capsule plus matching placebo
• Drug: GSK2248761 200 mg once daily
  2x100 mg capsules
• Drug: Efavirenz 600 mg once daily
  1x600mg tablet

• Experimental: GSK2248761 100 mg once daily
  In combination with either abacavir/lamivudine FDC qd or tenofovir/emtricitabine FDC qd
  Intervention: Drug: GSK2248761 100 mg once daily
• Experimental: GSK2248761 200 mg once daily
  In combination with either abacavir/lamivudine FDC qd or tenofovir/emtricitabine FDC qd
  Intervention: Drug: GSK2248761 200 mg once daily
• Active Comparator: Efavirenz 600 mg once daily
  In combination with either abacavir/lamivudine FDC qd or tenofovir/emtricitabine FDC qd
  Intervention: Drug: Efavirenz 600 mg once daily

Inclusion Criteria:

• HIV-1 infected adults greater than or equal to 18 years of age. A female is eligible to enter and participate in the study if she is (1) Non-childbearing potential, (2) Child-bearing potential, with a negative pregnancy test at screen and Day 1 and agrees to use protocol-specified methods of birth control while on study
• HIV-1 infection with a screening plasma HIV-1 RNA greater than or equal to 1000 copies/mL
• CD4+ cell count greater than or equal to 200 cells/mm3
• Antiretroviral-naive

Exclusion Criteria:

• Any pre-existing physical or mental condition (including substance abuse disorder) which, in the opinion of the Investigator, may interfere with the subject's ability to comply with the dosing schedule and/or protocol evaluations or which may compromise the safety of the subject
• Any condition which, in the opinion of the Investigator, may interfere with the absorption, distribution, metabolism or excretion of the drug or render the subject unable to take oral medication
• Women who are currently breastfeeding
• Any evidence of an active Centers for Disease and Prevention Control (CDC) Category C disease [CDC,1993], except cutaneous Kaposi's sarcoma not requiring systemic therapy
• History of ongoing or clinically relevant hepatitis within the previous 6 months, including chronic hepatitis B virus (HBV) infection (HBsAg positive). Asymptomatic individuals with chronic hepatitis C virus (HCV) infection will not be excluded, however Investigators must carefully assess if therapy specific for HCV infection is required; subjects who are anticipated to require such therapy during the randomized portion of the study must be excluded
• History of liver cirrhosis with or without hepatitis viral co-infection
• Ongoing or clinically relevant pancreatitis
• History of the following cardiac diseases: myocardial infarction, congestive heart failure, documented hypertrophic cardiomyopathy, sustained ventricular tachycardia
• Personal or known family history of prolonged QT syndrome
• History or presence of allergy or intolerance to the study drugs or their components, or a history of drug or other allergy that, in the opinion of the Principal Investigator, contraindicates their participation. In addition, if heparin is used during PK sampling, subjects with a history of sensitivity to heparin or heparin-induced thrombocytopenia should not be enrolled
• Evidence of viral resistance to any antiviral drug indicative of primary transmitted resistance in a screening or historical resistance test result
• Any acute laboratory abnormality at screening, which, in the opinion of the Investigator, would preclude the subject's participation in the study of an investigational compound. Any verified Grade 4 laboratory abnormality at screening would exclude a subject from study participation unless the Investigator can provide a compelling explanation for the laboratory result(s) and has the assent of the Medical Monitor
• Any of the following laboratory values at screening: (1) Creatinine clearance <50 mL/min via Cockroft-Gault method, (2) Alanine aminotransferase (ALT) greater than or equal to 5 times upper limits of normal (ULN). Subjects with ALT > 2x ULN but <5xULN may participate in the study, if in the opinion of the Investigator and GSK Medical Monitor the lab abnormality will not interfere with the study procedures or compromise subject safety, (3) Alanine aminotransferase (ALT) greater than or equal to 3xULN and bilirubin greater than or equal to 1.5xULN (with >35% direct bilirubin)
• Any clinically significant finding on screening ECG, specifically (a single repeat is allowed to determine eligibility): (1) Heart rate <45 and >100 beats per minute (bpm) (males); <50 and >100 bpm (females). Note: A heart rate from 100 to 110 bpm can be rechecked within 30 minutes to verify eligibility, (2) QRS duration > 120 msec, (3) QTc interval > 450 msec (4) Non-sustained (greater than or equal to 3 consecutive beats) or sustained ventricular tachycardia, (5) Sinus pauses > 2.5 seconds, (6) 2nd degree (Type II) or higher AV (Atrioventricular) block, (7) Evidence of WPW (Wolff- Parkinson-White) syndrome (ventricular preexcitation), (8) Pathologic Q waves (defined as Q wave > 40 msec OR depth >0.4 mV (9) Any other abnormality which in the opinion of the Investigator would interfere with the safety of the subject
• Treatment with any of the following agents within 28 days prior to screening, or has an anticipated need for these agents during the study (1) Radiation therapy or cytotoxic chemotherapeutic agents, (2) Immunomodulators (such as systemic corticosteroids, interleukins, or interferons) Note: Subjects using short-term (<7 day) steroid tapers and inhaled corticosteroids are eligible for enrollment (3) Any non-protocol-specified agent with documented activity against HIV 1 in vitro
• Treatment with an HIV-1 immunotherapeutic vaccine within 90 days prior to screening
• Receipt of an experimental drug and/or vaccine within 28 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
• Immunization within 28 days prior to first dose of IP