A Study of the Pharmacokinetics and Antiviral Activity of Dolutegravir in the Central Nervous System in HIV-1 Infected ART-naive Subjects

• The antiviral activity of dolutegravir in plasma over time using proportions of subjects with HIV-1 RNA <50 copies/milliliter (c/mL) as well as absolute values and changes from Baseline in HIV-1 RNA levels. [ Time Frame: through Week 96 ] [ Designated as safety issue: No ]
• The antiviral activity of dolutegravir in CSF over time using absolute values and changes from Baseline in HIV-1 RNA levels. [ Time Frame: Week 2 and Week 16 ] [ Designated as safety issue: No ]
• The relationship between dolutegravir concentrations in CSF and HIV-1 RNA in CSF. [ Time Frame: Week 2 and Week 16 ] [ Designated as safety issue: No ]
• The relationship between HIV-1 RNA suppression in plasma and CSF. [ Time Frame: Week 2 and Week 16 ] [ Designated as safety issue: No ]
• The numbers of subjects with clinical adverse events or laboratory abnormalities as a measure of the safety and tolerability of dolutegravir. [ Time Frame: through Week 96 ] [ Designated as safety issue: No ]
• Changes in immunologic functions (CD4/CD8 cellcounts) using absolute values and changes from Baseline. [ Time Frame: through Week 96 ] [ Designated as safety issue: No ]
• The incidence of HIV-associated conditions. [ Time Frame: through Week 96 ] [ Designated as safety issue: No ]
• The development of viral resistance in subjects experiencing virologic failure. [ Time Frame: through Week 96 ] [ Designated as safety issue: No ]

ING116070 is a Phase IIIb single-arm, open-label, multicenter study. The study will be conducted in approximately 14 HIV-1 infected antiretroviral therapy (ART)-naïve subjects. Subjects who fulfill eligibility requirements will receive dolutegravir (DTG) 50 mg once daily in combination with the fixed dose dual nucleoside reverse transcripatase inhibitor(NRTI) abacavir/lamivudine (ABC/3TC) for 96 weeks. One pair of pharmacokinetic (PK) samples in plasma and cerebral spinal fluid (CSF) (matching time) for determination of DTG concentration will be collected at Week 2 and Week 16. Samples for plasma HIV-1 RNA will be collected at Baseline and various time points throughout the study and samples for HIV-1 RNA levels in the CSF will be collected at Baseline, Week 2 and Week 16. Safety, additional measures of antiviral activity and development of viral resistance will also be evlauated. The primary analysis will take place after the last subject completes 16 weeks on therapy; additional analyses will be conducted after the last subject completes Weeks 2 and 96 (end of study).

ING116070 is a Phase IIIb single-arm, open-label, multicenter study. The study will be conducted in approximately 14 HIV-1 infected antiretroviral therapy (ART)-naïve subjects. Subjects who meet all screening requirements may enter the study and initiate treatment as soon as all screening procedures have been completed and results are available and on file. The 14-day screening period may be extended to 28 days to allow receipt of all Screening assessment results and to accommodate scheduling.

Subjects who fulfill eligibility requirements will receive dolutegravir (DTG) 50 mg once daily in combination with the fixed dose dual nucleoside reverse transcripatase inhibitor(NRTI) abacavir/lamivudine ABC/3TC for 96 weeks. One pair of pharmacokinetic (PK) samples in plasma and CSF (matching time) for determination of DTG concentration will be collected at Week 2 and Week 16. Samples for plasma HIV-1 RNA will be collected at Baseline and various time points throughout the study and samples for HIV-1 RNA levels in the CSF will be collected at Baseline, Week 2 and Week 16. Safety, additional measures of antiviral activity and development of viral resistance will also be evlauated. The primary analysis will take place after the last subject completes 16 weeks on therapy; additional analyses will be conducted after the last subject completes Weeks 2 and 96 (end of study).

Subjects are considered to have completed the study if they remain on therapy (i.e., have not permanently discontinued investigational product [IP]) and complete the Treatment Phase, including the Week 96 visit.

Inclusion Criteria:

• HIV-1 infected adults at least 18 years of age. Females are eligible to enter and participate in the study if she is (1) of non-childbearing potential or (2) of childbearing potential with a negative pregnancy test at Screening and Day 1 and agrees to use protocol-defined methods of birthcontrol while on the study.
• HIV-1 infection as documented by Screening plasma HIV-1 RNA greater than or equal to 5000 copies/mL
• CD4+ cell count greater than or equal to 200 cells/mm3
• Antiretroviral-naive (less than or equal to 10 days of prior therapy with any antiretroviral agent following diagnosis of HIV-1 infection)
• Signed and dated written informed consent is obtained from the subject or the subject's legal representative prior to screening
• Documentation that the subject has been screened for, and is negative for the HLA-B*5701 allele
• Is willing to undergo serial lumbar punctures

Exclusion Criteria:

• Relative or absolute contraindication to lumbar puncture, such as current coagulopathy, thrombocytopenia (platelets less than 50,000/microliter), hemophilia, or use of anticoagulant medication
• Moderate or severe cognitive impairment
• Women who are pregnant or breastfeeding
• Any evidence of an active Center for Disease Control and Prevention (CDC) Category C disease, except cutaneous Kaposi's sarcoma not requiring systemic therapy or historic CD4+ cell levels less than 200cells/mm3
• Subjects with any degree of hepatic impairment
• Positive for Hepatitis B at screening (+HbsAg), or an anticipated need for Hepatitis C virus (HCV) therapy during the study
• History or presence of allergy or intolerance to the study drugs or their components or drugs of their class
• History of malignancy within the past 5 years or ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma; other localized malignancies require agreement between the investigator and the Study medical monitor for inclusion of the subject
• Recent history (less than or equal to 3 months) of any upper or lower gastrointestinal bleed, with the exception of anal or rectal bleeding
• Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening
• Treatment with any of the following agents within 28 days of Screening: radiation therapy, cytotoxic chemotherapeutic agents, any immunomodulators that alter immune responses
• Treatment with any agent, except recognized ART as allowed above, with documented activity against HIV-1 in vitro within 28 days of first dose of IP
• Exposure to an experimental drug or experimental vaccine within either 28 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, whichever is longer, prior to the first dose of IP
• Any evidence of primary viral resistance based on the presence of any major resistance-associated mutation in the Screening result or, if known, any historical resistance test result. Note: retests of Screening genotypes are not allowed
• Any verified Grade 4 laboratory abnormality (a single repeat test is allowed during the Screening period to verify a 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 is exclusionary
• Alanine aminotransferase (ALT) greater than 5 times the upper limit of normal (ULN)
• ALT greater than or equal to 3xULN and bilirubin greater than or equal to 1.5xULN (with greater than 35% direct bilirubin)
• Subject has creatinine clearance of less than 50 mL/min via Cockroft-Gault method

• Shionogi
• GlaxoSmithKline