A Dose Ranging Trial of GSK1349572 and 2 NRTI in HIV-1 Infected, Therapy Naive Subjects

A Phase IIb Study to Select a Once Daily Dose of GSK1349572 Administered With Either Abacavir/Lamivudine or Tenofovir/Emtricitabine in HIV-1 Infected Antiretroviral Therapy Naive Adult Subjects

This Phase IIb study in HIV-infected antiretroviral naive subjects will select an optimal once daily dose of GSK1349572 from a range of doses for future evaluation.

This Phase IIb study in HIV-infected antiretroviral naive adult subjects will include a dose-ranging evaluation of GSK1349572 10mg, 25mg and 50mg once daily blinded doses and a control arm of open label efavirenz 600mg once daily. Background ART for all study subjects will be chosen by the investigators and will be either Truvada or Epzicom/Kivexa. Data from the three doses of GSK1349572 will be compared on the basis of antiviral activity, safety/tolerability and pharmacokinetics over 16-24 weeks.

Several planned interim analyses will evaluate data in real time; any doses considered inferior will be dropped and subjects on those doses of GSK1349572 will have the option to switch to either the highest dose still under investigation or the selected dose. Subjects will be able to remain in the study, unless they reach a stopping criterion, for at least 96 weeks.

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

Inclusion Criteria:

• HIV-1 infected male or female adults at least 18 years of age. Women capable of becoming pregnant must use appropriate contraception during the study (as defined by the protocol);
• HIV-1 infection with a screening plasma HIV-1 RNA greater than or equal to 1000copies/mL;
• CD4+ cell count greater than or equal to 200cells/mm3 (or higher as local guidelines dictate);
• ART-naive (less than or equal to 10 days of prior therapy with any antiretroviral agent). Any previous exposure to an HIV integrase inhibitor other than GSK1349572 will be exclusionary.
• No evidence of viral resistance to any antiretroviral drug indicative of primary transmitted resistance at screening;
• Able to understand and comply with protocol requirements;
• Able to provide written informed consent prior to screening;
• French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

Note: Subjects starting abacavir as part of the NRTI backbone must have been screened and be negative for the HLA-B*5701 allele.

Exclusion Criteria:

• Any pre-existing or serious mental or physical disorder which could compromise ability to comply with the protocol or compromise subject safety;
• Women who are pregnant or breastfeeding;
• An active AIDS-defining condition at the screening visit;
• Previous participation in an experimental drug and/or vaccine trial(s) within 30 days or 5 half-lives;
• History of clinically relevant pancreatitis or hepatitis within the previous 6 months, including HBsAg positive result. Asymptomatic HCV infection will not be exclusionary, however subject who will require HCV therapy during the trial should be excluded. Any subject with a history of liver cirrhosis with or without hepatitis viral co-infection will be excluded.
• Any condition which could interfere with the absorption, distribution, metabolism or excretion of the drug;
• Any acute or Grade 4 laboratory abnormality at screening;
• History of upper gastrointestinal bleed and/or subjects with active peptic ulcer disease;
• Estimated creatinine clearance <50 mL/min;
• Alanine aminotransferase (ALT) greater than or equal to 5 times ULN;
• Alanine aminotransferase (ALT) greater than or equal to 3xULN and bilirubin greater than or equal to 1.5xULN (with >35% direct bilirubin);
• Lipase greater than or equal to 3xULN;
• Hemoglobin < 100 g/L(10 g/dL);
• History of allergy to the study drugs or their components or drugs of their class;
• Treatment with radiation therapy, cytotoxic chemotherapeutic agents, any agents with activity against HIV-1 or immunomodulators within 28 days prior to screening;
• Treatment with an HIV-1 immunotherapeutic vaccine within 90 days prior to screening;
• History of protocol-defined cardiac diseases;
• Personal or family history of prolonged QT syndrome;
• Any clinically significant finding, as specified in the protocol, on electrocardiograph (ECG);
• Significant blood loss in excess of 500 mL within a 56 day period prior to screening visit;
• Immunization within 30 days prior to first dose of investigational product;
• French subjects: The subject has participated in any study using an investigational drug during the previous 60 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 for the study or the subject will participate simultaneously in another clinical study.