Dose-finding Study of GSK2248761 in Antiretroviral Therapy-experienced Subjects With NNRTI-resistant HIV Infection
Condition: Infection, Human Immunodeficiency Virus
MeSH terms: Infections; HIV Infections; Acquired Immunodeficiency Syndrome
Intervention: GSK2248761 100 mg once daily; GSK2248761 200 mg once daily; Etravirine
Intervention description: 1 100mg capsule OAD plus matching placebo; 2 100mg capsules OAD; 2 100mg tablets twice daily
Intervention MeSH terms: Etravirine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 30.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: raltegravir; NNRTI; ritonavir; darunavir; HIV; GSK2248761; antiretroviral; HIV Infection; HAART

Summary:

      This 48 week, phase 2b study in 150 HIV-1 infected antiretroviral therapy experienced 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 etravirine (ETV) 200 mg twice daily. The
      background ART for all three arms will be darunavir/ritonavir (DRV/r) 600 mg/100 mg twice
      daily plus raltegravir (RAL) 400 mg twice daily. 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. Females are eligible
             to enter and participate in the study if she is (1) non-childbearing potential, (2)
             child bearing potential with negative pregnancy test at screening 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
             400copies/mL

          -  Previously received or current treatment with antiretroviral therapy (HAART) for HIV-1
             infection (patient may be off ART at time of screening)

          -  HIV-1 harboring NNRTI resistance by screening genotype (defined as the presence of at
             least 1 NNRTI resistance-associated mutations)

        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

          -  HIV-1 genotype results with any of the following will be excluded: (1)Any screening
             genotype with virus showing a Y181 mutation in combination with any other NNRTI
             resistance-associated mutations, (2) Any screening genotype with virus showing a Y181I
             or Y188L alone or in combination with any other NNRTI resistance-associated mutations

          -  HIV-1 phenotype results with any of the following will be excluded: (1) Any screening
             phenotype with virus showing etravirine fold change >10, (2) Any screening phenotype
             with virus showing darunavir fold change > 20, (3) Any screening phenotype with virus
             showing raltegravir fold change >1.5

          -  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 ULN. Subjects with ALT >2xULN 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 electrocardiograph (ECG), specifically
             (a single repeat is allowed to determine eligibility): (1) Heart rate <45 and >100bpm
             (males), <50 and >100bpm (females); Note: A heart rate from 100 to 110 BPM can be
             rechecked within 30 minutes to verify eligibility, (2) QRS duration >120msec, (3) QTc
             interval >450msec, (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
             >40msec 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