Dose-finding Study of GSK2248761 in Antiretroviral Therapy-Naive Subjects (SIGNET)
Condition: Infection, Human Immunodeficiency Virus
MeSH terms: Infections; Acquired Immunodeficiency Syndrome; HIV Infections; Immunologic Deficiency Syndromes
Intervention: GSK2248761 100 mg once daily; GSK2248761 200 mg once daily; Efavirenz 600 mg once daily
Intervention description: 1x100 mg capsule plus matching placebo; 2x100 mg capsules; 1x600mg tablet
Intervention MeSH terms: Efavirenz
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 23.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: antiretroviral; HAART; NNRTI; emtricitabine; Sexually Transmitted Disease; antiretroviral therapy (ART)-naive adults; Immunologic Deficiency Syndrome; tenofovir; abacavir; Retroviridae Infections; GSK2248761; lamivudine; Acquired ImmunoDeficiency Syndrome (AIDS); HIV infection; efavirenz

Summary:

      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.
    

Eligibility criteria:

        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