A Study of the Pharmacokinetics and Antiviral Activity of Dolutegravir in the Central Nervous System in HIV-1 Infected ART-naive Subjects
Condition: Infection, Human Immunodeficiency Virus
MeSH terms: Acquired Immunodeficiency Syndrome; HIV Infections
Intervention: Dolutegravir
Intervention description: 50mg Once Daily
Intervention MeSH terms: Dolutegravir
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 13.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: cerebrospinal fluid (CSF); ART-naive; integrase inhibitor; dolutegravir; antiretroviral therapy naive

Summary:

      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).
    

Eligibility criteria:

        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