Phase IIa Dose-ranging Study of GSK1349572 in HIV-1 Infected Adults

A Phase 2a, Multicenter, Randomized, Parallel, Double-Blind, Dose Ranging, Placebo-Controlled Study to Compare Antiviral Effect, Safety, Tolerability and Pharmacokinetics of GSK1349572 Monotherapy Versus Placebo Over 10 Days in HIV-1 Infected Adults (ING111521)

GSK1349572 is an integrase inhibitor that will be evaluated for the treatment of HIV infection. This phase IIa, multicenter, randomized, parallel, double-blind, dose ranging, placebo-controlled 'proof of concept' study is to be conducted to compare antiviral effect, safety, tolerability, and pharmacokinetics of GSK1349572 monotherapy versus placebo over 10 days in ART-naïve and experienced, but integrase inhibitor naïve (meaning never having had an integrase inhibitor) HIV-1 infected adults who are not currently receiving antiretroviral therapy. This study consists of a screening visit, a treatment period and a follow-up evaluation. Thirty subjects will be randomized to receive one of three doses of GSK1349572 or placebo q24h over 10 days. Antiviral effect measures include viral load and CD4 cell count.

Inclusion Criteria:

• Male or female >/18 and </ 65 years of age.
• A female subject is eligible to participate if she is of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation, hysterectomy or bilateral oophorectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<140 pmol/L) is confirmatory]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in Section 8.1 if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.
• Male subjects must agree to use one of the contraception methods listed in Section 8.1. This criterion must be followed from the time of the first dose of study medication until 14 days after the last dose of study drug.
• CD4+ cell count >/ 100 cells/mm3.
• Documented HIV-1 infection and a screening plasma HIV-1 RNA >/ 5000 copies/mL.
• No current antiretroviral therapy and have not received any in the 12 weeks prior to first dose.
• Capable of giving written informed consent, which includes compliance

Exclusion Criteria:

• The subject has a positive pre-study drug screen. Drugs that will be screened for include amphetamines, barbiturates, cocaine, and PCP.
• The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
• 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 investigator or GSK Medical Monitor, 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.
• Prior treatment with an integrase inhibitor (> 1 dose).
• Treatment with radiation therapy or cytotoxic chemotherapeutic agents within 30 days of study drug administration or anticipated need for such treatment within the study.
• Treatment with immunomodulating agents (such as systemic corticosteroids, interleukins, interferons) or any agent with known anti-HIV activity (such as hydroxyurea or foscarnet) within 30 days of study drug administration
• Treatment with any vaccine within 30 days prior to receiving study medication.
• Use of multivitamins or antacids within 24 hours prior to the first dose of investigational product.
• History of regular alcohol consumption within 6 months of the screening visit defined as: an average weekly intake of >14 drinks/week for men or >7 drinks/week for women. One drink is equivalent to (12 g alcohol) = 5 ounces (150 ml) of wine or 12 ounces (360 ml) of beer or 1.5 ounces (45 ml) of 80 proof distilled spirits.
• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
• Pregnant females as determined by positive urine/serum hCG test at screening or prior to dosing.
• Lactating females.
• Unwillingness or inability to follow the procedures outlined in the protocol.
• Any condition (including alcohol or drug abuse) which, in the opinion of the investigator, could interfere with the subject's ability to comply with the dosing schedule and protocol evaluations or which might compromise the safety of the subject.
• An active Center for Disease Control and Prevention (CDC) Category C disease [see Appendix 1], except cutaneous Kaposi's sarcoma not requiring systemic therapy during the trial.
• History of clinically relevant pancreatitis or hepatitis within the previous 6 months.
• Subjects with a pre-existing condition interfering with normal gastrointestinal anatomy or motility, hepatic and/or renal function, that could interfere with the absorption, metabolism, and/or excretion of the study drugs.
• 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.
• Inadequate renal function at Screening, defined as either a serum creatinine >1.5 mg/dL or a calculated creatinine clearance (CrCl) ≤ 50 mL/min. A single repeat serum creatinine is allowed to determine eligibility.
• Any acute laboratory abnormality at screen which, in the opinion of the investigator, should preclude the subject's participation in the study of an investigational compound. Any grade 4 laboratory abnormality at screen, with the exception of CPK, will 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 sponsor. A single repeat is allowed for eligibility determination.
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3x times the upper limit of normal. A single repeat of ALT and/or AST is allowed for eligibility determination.
• Exclusion Criteria for Screening ECG (A single repeat is allowed for eligibility determination):