Safety and Tolerability Study to Evaluate Lower Dose of GSK2248761 in Antiretroviral Treatment-Naive HIV-1 Infected Adults.
Condition: Infection, Human Immunodeficiency Virus
MeSH terms: Acquired Immunodeficiency Syndrome; HIV Infections
Intervention: GSK2248761; Lopinavir/ritonavir; HAART; Placebo; GSK2248761
Intervention description: GSK2248761 30 mg capsule once a day for 7 days. GSK2248761 is an investigational (not approved by the FDA) HIV drug in the class of non-nucleoside reuptake inhibitor class.; Lopinavir 400 mg and ritonovir 100 mg every 12 hours for 28 days. Lopinavir/ritonavir is approved by the FDA as an HIV medication in the protease inhibitor class. Kaletra is a trademark of Abbott Laboratories.; Highly Active Antiretroviral therapy of the doctor's choice.; Placebo is a capsule with no drug in it.; GSK2248761 10 mg -20 mg or 40 mg - 90 mg once a day for 7 days. GSK2248761 is an investigational (not approved by the FDA) HIV drug in the class of non-nucleoside reuptake inhibitor class.
Intervention MeSH terms: Ritonavir; Lopinavir
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 8.0
Sex: All
Minimum age: 21 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: IDX12899; adaptive; monotherapy; pharmacokinetics; Treatment-naive; HIV-1; GSK2248761; NNRTI; HIV Infections; treatment naive

Summary:

      GSK has in-licensed a novel NNRTI-class candidate (GSK2248761, IDX12899) for the treatment of
      subjects with HIV-1 infection from Idenix Pharmaceuticals. Idenix Pharmaceuticals completed a
      proof-of-concept study evaluating GSK2248761 monotherapy over seven days in forty
      treatment-naïve subjects infected with HIV-1. GSK2248761 doses sequentially evaluated were
      800 mg QD, 400 mg QD, 200 mg QD and 100mg QD.

      This study will evaluate a lower dose, or doses, of GSK2248761 to better characterize the
      dose-response and concentration-response curves. The results from this study will be used to
      select doses for future clinical studies in HIV-1 infected subjects.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or Female, 21 to 65 years of age.

          -  Female of non-childbearing potential defined as: being post-menopausal, defined as 12
             months of spontaneous amenorrhea and having a serum FSH level >40 MIU/ml at Screening
             OR have had a documented bilateral tubal ligation or hysterectomy of at least 6 months
             prior to study initiation, bilateral oophorectomy or bilateral tubal ligation.

          -  Plasma HIV-1 RNA value >= 5000 copies/mL.

          -  CD4+ count >= 200 cells/mm3.

          -  Is antiretroviral treatment-naïve and agrees not to start antiretroviral therapy prior
             to clinic check-in (Day-1).

          -  Subject agrees to start a standard HAART regimen on Day 8 of the study or Kaletra
             monotherapy for 28 days within 24 hours after the last dose of study medication.

          -  Capable of giving written informed consent, which includes being willing and able to
             comply with the requirements and restrictions listed in the consent form.

        Exclusion Criteria:

          -  Subject is pregnant as determined by a positive urine/serum pregnancy test at
             Screening and Day -1.

          -  Lactating females.

          -  Male subjects of reproductive potential and unwilling to use double barrier method of
             contraception (e.g., condom plus spermicide) and continue to use an adequate method of
             birth control for at least 30 days after the last dose of the study drug.

          -  Has a positive screening Hepatitis B surface antigen, positive screening Hepatitis C
             virus (HCV) antibody and detectable HCV ribonucleic acid (RNA) on subsequent testing.
             If the Hepatitis C antibody is positive but the HCV RNA is undetectable, the subject
             may be included in the study.

          -  History of regular alcohol consumption within 6 months of Screening as defined as: an
             average weekly intake of >21 units for males or >14 units for females. One unit is
             equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 ml) of wine
             or 1 (25 ml) measure of spirits

          -  Has a positive pre-study drug screen. Drugs that will be screened for include
             amphetamines, barbiturates, cocaine and PCP.

          -  History of sensitivity to any of the study medications, or components thereof, 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.

        Note: Study drugs include GSK2248761 placebo or the follow-up HAART or Kaletra therapy.

          -  Received an immunomodulating agent (e.g., interleukin-2) or immunotherapeutic vaccine
             within 30 days before Day -1.

          -  Requires a medication that is a known substrate, inhibitor and/or inducer of CYP3A4.

          -  Has received an investigational drug or participated in any other research trial
             within 30 days or 5 half-lives, or twice the duration of the biological effect of any
             drug (whichever is longer) prior to the first dosing day.

          -  Has ever had an AIDS-defining illness.

          -  Has a history of or has a currently active clinically important disease other than
             HIV-1 infection that, in the opinion of the Investigator, may put the subject at risk
             because of participation in this study (including renal and hepatic impairment, active
             infections including tuberculosis or opportunistic infection, malignancy and cardiac
             dysfunction).

          -  Has an intestinal malabsorption (e.g., structural defects, digestive failure, enzyme
             deficiencies, etc).

          -  Has a pre-existing NNRTI drug resistance based on genotyping at Screening.

          -  Where participation in the study would result in donation of blood or blood products
             in excess of 500mL within a 56 day period.

          -  Subject has any of the following laboratory parameters at Screening (a single repeat
             is allowed for eligibility determination): Hemoglobin <8.5 g/dL, Neutrophil count
             <1000 cells/mm3, Platelet count <100,000 cells/mm3, Serum creatinine > the upper limit
             of normal (ULN), AST or ALT <= 2.5 x ULN.

          -  Exclusion Criteria for Screening ECG (A single repeat is allowed for eligibility
             determination): Exclusion Criteria for Screening ECG: Heart rate: (males) <45 and >100
             bpm (females) <50 and >100 bpm, QRS duration: >120 msec, QTc interval (Bazett): > 450
             msec. Non-sustained (>= 3 consecutive beats) or sustained ventricular tachycardia.
             Sinus Pauses >2.5 seconds. 2nd degree (Type II) or higher AV block. Evidence of
             previous myocardial infarction (pathologic Q waves, S-T segment changes (except early
             repolarization)).